COMBINATIONS FOR GENERATING TUMOR-SPECIFIC IMMUNOLOGICAL

MEMORY

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of U.S. provisional patent application no.

62/142,961, filed April 3, 2015, the contents of which are herein incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

[0002] Bruton's tyrosine kinase (BTK), a member of the Tec family of non-receptor tyrosine kinases, is a key signaling enzyme expressed in all hematopoietic cells types except T lymphocytes and natural killer cells. Btk plays an essential role in the B-cell signaling pathway linking cell surface B-cell receptor (BCR) stimulation to downstream intracellular responses.

[0003] l-((R)-3-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyri midin-l- yl)piperidin-l-yl)prop-2-en-l-one is also known by its IUPAC name as l-{(3R)-3-[4-amino- 3 -(4-phenoxyphenyl)- lH-pyrazolo[3 ,4-<i]pyrimidin- 1 -yljpiperidin- 1 -yl }prop-2-en- 1 -one or 2- Propen- 1 -one, 1 -[(3R)-3 -[4-amino-3 -(4-phenoxyphenyl)- lH-pyrazolo[3 ,4-<i]pyrimidin- 1 -yl]- 1-piperidinyl-, and has been given the US AN name, ibrutinib. The various names given for ibrutinib are used interchangeably herein.

SUMMARY OF THE INVENTION

[0004] Disclosed herein, in some embodiments, are methods of inducing tumor- specific immunological memory in a cancer comprising, administering an

immunomodulating agent and a Bruton's tyrosine kinase (Btk) inhibitor. In some

embodiments, the immunomodulating agent is an anti-CTLA-4 antibody.

[0005] Disclosed herein, in some embodiments, are methods of inducing tumor- specific immunological memory in a cancer comprising, administering an

immunomodulating agent and a Bruton's tyrosine kinase (Btk) inhibitor. In some

embodiments, the immunomodulating agent is a small molecule or an antibody. In some embodiments, the immunomodulating agent is a small molecule inhibitor. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some embodiments, the immunomodulating agent is a CTLA-4 inhibitor. In some embodiments, the CTLA-4 inhibitor is an antibody. In some embodiments, the CTLA-4 inhibitor is a monoclonal antibody. In some embodiments, the CTLA-4 inhibitor is ipilimumab. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the

immunomodulating agent is an inhibitor of TEVI3. In some embodiments, the Btk inhibitor is ibrutinib. In some embodiments, the administering comprises daily dosing of the

immunomodulating agent and the Btk inhibitor for at least 7 days. In some embodiments, the administering comprises dosing of the immunomodulating agent and the Btk inhibitor for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, 10 days, at least 14 days, at least 21 days, at least 28 days, at least 30 days, at least 35 days, at least 42 days, at least 49 days, at least 56 days, at least 60 days, at least 70 days, or at least 90 days. In some embodiments, the Btk inhibitor is administered once a day, two times per day, three times per day, four times per day, or five times per day. In some embodiments, the immunomodulating agent is administered once every five days, once every three days, once every two days, once a day, two times per day, three times per day, four times per day, or five times per day. In some embodiments, the Btk inhibitor is administered once per day and the immunomodulating agent is administered every two days. In some embodiments, the Btk inhibitor is administered once per day for 27 days and the

immunomodulating agent is administered every two days for 17 days. In some embodiments, the Btk inhibitor is administered at a dosage of about 40 mg/day to about 1000 mg/day. In some embodiments, the Btk inhibitor is administered orally. In some embodiments, the Btk inhibitor and the immunomodulating agent are administered simultaneously, sequentially, or intermittently. In some embodiments, the immunomodulating agent is an antibody. In some embodiments, the immunomodulating agent is a monoclonal antibody. In some embodiments, the immunomodulating agent is ipilimumab. In some embodiments the administering results in an increase in secretion of IFNy and/or an increase in tumor infiltration by Ki67 ⁺ / ΙΠΝΓγ ⁺ CD4 ⁺ and CD8 ⁺ T cells. In some embodiments, the cancer is a hematological malignancy or a solid tumor. In some embodiments, the cancer is a relapsed or refractory cancer. In some embodiments, the cancer is metastasized. In some embodiments, the hematological malignancy is a leukemia, a lymphoma, a myeloma, a non-Hodgkin's lymphoma, a

Hodgkin's lymphoma, or a B-cell malignancy. In some embodiments, the B-cell malignancy is follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt' s lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis. In some embodiments, the B-cell malignancy is diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), B cell prolymphocytic leukemia (B-PLL), non-CLL/SLL lymphoma, mantle cell lymphoma, multiple myeloma, Waldenstrom's macroglobulinemia, or a combination thereof. In some embodiments, the B- cell malignancy is diffuse large B-cell lymphoma (DLBCL). In some embodiments, DLBCL is activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL). In some embodiments, the B-cell malignancy is a relapsed or refractory B-cell malignancy. In some embodiments, the relapsed or refractory B-cell malignancy is diffuse large B-cell lymphoma (DLBCL). In some embodiments, the relapsed or refractory DLBCL is activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL). In some embodiments, the relapsed or refractory B-cell malignancy is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), B cell prolymphocytic leukemia (B-PLL), non-CLL/SLL lymphoma, mantle cell lymphoma, multiple myeloma, Waldenstrom's macroglobulinemia, or a combination thereof. In some embodiments, the B-cell malignancy is a metastasized B-cell malignancy. In some

embodiments, the metastasized B-cell malignancy is diffuse large B-cell lymphoma

(DLBCL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), B cell prolymphocytic leukemia (B-PLL), non-CLL/SLL lymphoma, mantle cell lymphoma, multiple myeloma, Waldenstrom's macroglobulinemia, or a combination thereof. In some embodiments, the cancer is a solid tumor. In some embodiments, the solid tumor is a sarcoma, or carcinoma. In some embodiments, the cancer is selected from anal cancer;

appendix cancer; bile duct cancer (i.e., cholangiocarcinoma); bladder cancer; breast cancer; cervical cancer; colon cancer; cancer of Unknown Primary (CUP); esophageal cancer; eye cancer; fallopian tube cancer; gastroenterological cancer; kidney cancer; liver cancer; lung cancer; medulloblastoma; melanoma; oral cancer; ovarian cancer; pancreatic cancer;

parathyroid disease; penile cancer; pituitary tumor; prostate cancer; rectal cancer; skin cancer; stomach cancer; testicular cancer; throat cancer; thyroid cancer; uterine cancer; vaginal cancer; or vulvar cancer. In some embodiments, the cancer is selected from bladder cancer, breast cancer, colon cancer, gastroenterological cancer, kidney cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, proximal or distal bile duct cancer, and melanoma. In some embodiments, the cancer is selected from bladder cancer, breast cancer, colon cancer, gastroenterological cancer, kidney cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, proximal or distal bile duct cancer, and melanoma. In some embodiments, the relapsed or refractory cancer is selected from bladder cancer, breast cancer, colon cancer, gastroenterological cancer, kidney cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, proximal or distal bile duct cancer, and melanoma. In some embodiments, the metastasized cancer is selected from bladder cancer, breast cancer, colon cancer, gastroenterological cancer, kidney cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, proximal or distal bile duct cancer, and melanoma. In some embodiments, the cancer is a colon cancer. In some embodiments, the colon cancer is adenocarcinoma, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors, primary colorectal lymphoma, leiomyosarcoma, melanoma, squamous cell-carcinoma, mucinous

adenocarcinoma, or Signet ring cell adenocarcinoma. In some embodiments, the cancer is a breast cancer. In some embodiments, the breast cancer is ductal carcinoma in situ, lobular carcinoma in situ, invasive or infiltrating ductal carcinoma, invasive or infiltrating lobular carcinoma, inflammatory breast cancer, triple-negative breast cancer, paget disease of the nipple, phyllodes tumor, angiosarcoma or invasive breast carcinoma. In some embodiments, the method further comprises administering an additional anticancer agent. In some embodiments, the additional anticancer agent is selected from among a chemotherapeutic agent, radiation therapy, immunotherapy, or a combination thereof. In some embodiments, the chemotherapeutic agent is selected from among chlorambucil, ifosfamide, doxorubicin, mesalazine, thalidomide, lenalidomide, temsirolimus, everolimus, fludarabine, fostamatinib, paclitaxel, docetaxel, ofatumumab, rituximab, dexamethasone, prednisone, CAL-101, ibritumomab, tositumomab, bortezomib, pentostatin, endostatin, or a combination thereof.

[0006] Disclosed herein, in some embodiments, are methods of inducing tumor- specific immunological memory in a cancer comprising, administering a CTLA-4 inhibitor and ibrutinib. In some embodiments, the administering comprises daily dosing of the CTLA- 4 inhibitor and ibrutinib for at least 7 days. In some embodiments, the administering comprises daily dosing of the CTLA-4 inhibitor and ibrutinib for at least 7 days. In some embodiments, the administering comprises dosing of the CTLA-4 inhibitor and ibrutinib for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, 10 days, at least 14 days, at least 21 days, at least 28 days, at least 30 days, at least 35 days, at least 42 days, at least 49 days, at least 56 days, at least 60 days, at least 70 days, or at least 90 days. In some embodiments, the ibrutinib is administered once a day, two times per day, three times per day, four times per day, or five times per day. In some embodiments, the CTLA-4 inhibitor is administered once every five days, once every three days, once every two days, once a day, two times per day, three times per day, four times per day, or five times per day. In some embodiments, the ibrutinib is administered once per day and CTLA-4 inhibitor is administered every two days. In some embodiments, the ibrutinib is administered once per day for 27 days and the CTLA-4 inhibitor is administered every two days for 17 days. In some embodiments, ibrutinib is administered at a dosage of about 40 mg/day to about 1000 mg/day. In some embodiments, ibrutinib is administered orally. In some embodiments, ibrutinib and the CTLA-4 inhibitor are administered simultaneously, sequentially, or intermittently. In some embodiments, the CTLA-4 inhibitor is an antibody. In some embodiments, the CTLA-4 inhibitor is a monoclonal antibody. In some

embodiments, the CTLA-4 inhibitor is ipilimumab. In some embodiments the administering results in an increase in secretion of ΠΤΝΓγ and/or an increase in tumor infiltration by Ki67 ⁺ / IFNy CD4 ⁺ and CD8 ⁺ T cells. In some embodiments, the cancer is a hematological malignancy or a solid tumor. In some embodiments, the cancer is a relapsed or refractory cancer. In some embodiments, the cancer is metastasized. In some embodiments, the hematological malignancy is a leukemia, a lymphoma, a myeloma, a non-Hodgkin's lymphoma, a Hodgkin's lymphoma, or a B-cell malignancy. In some embodiments, the B- cell malignancy is follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt's lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B cell prolymphocyte leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis. In some embodiments, the B-cell malignancy is diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), B cell prolymphocytic leukemia (B-PLL), non-CLL/SLL lymphoma, mantle cell lymphoma, multiple myeloma, Waldenstrom's macroglobulinemia, or a combination thereof. In some embodiments, the B-cell malignancy is diffuse large B-cell lymphoma (DLBCL). In some embodiments, DLBCL is activated B-cell diffuse large B-cell lymphoma (ABC- DLBCL). In some embodiments, the B-cell malignancy is a relapsed or refractory B-cell malignancy. In some embodiments, the relapsed or refractory B-cell malignancy is diffuse large B-cell lymphoma (DLBCL). In some embodiments, the relapsed or refractory DLBCL is activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL). In some embodiments, the relapsed or refractory B-cell malignancy is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), B cell prolymphocytic leukemia (B-PLL), non-CLL/SLL lymphoma, mantle cell lymphoma, multiple myeloma, Waldenstrom's macroglobulinemia, or a combination thereof. In some embodiments, the B-cell malignancy is a metastasized B-cell malignancy. In some embodiments, the metastasized B-cell malignancy is diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), B cell prolymphocytic leukemia (B-PLL), non-CLL/SLL lymphoma, mantle cell lymphoma, multiple myeloma, Waldenstrom's macroglobulinemia, or a combination thereof. In some embodiments, the cancer is a solid tumor. In some embodiments, the solid tumor is a sarcoma, or carcinoma. In some embodiments, the cancer is selected from anal cancer;

appendix cancer; bile duct cancer (i.e., cholangiocarcinoma); bladder cancer; breast cancer; cervical cancer; colon cancer; cancer of Unknown Primary (CUP); esophageal cancer; eye cancer; fallopian tube cancer; gastroenterological cancer; kidney cancer; liver cancer; lung cancer; medulloblastoma; melanoma; oral cancer; ovarian cancer; pancreatic cancer;

parathyroid disease; penile cancer; pituitary tumor; prostate cancer; rectal cancer; skin cancer; stomach cancer; testicular cancer; throat cancer; thyroid cancer; uterine cancer; vaginal cancer; or vulvar cancer. In some embodiments, the cancer is selected from bladder cancer, breast cancer, colon cancer, gastroenterological cancer, kidney cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, proximal or distal bile duct cancer, and melanoma. In some embodiments, the cancer is selected from bladder cancer, breast cancer, colon cancer, gastroenterological cancer, kidney cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, proximal or distal bile duct cancer, and melanoma. In some embodiments, the relapsed or refractory cancer is selected from bladder cancer, breast cancer, colon cancer, gastroenterological cancer, kidney cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, proximal or distal bile duct cancer, and melanoma. In some embodiments, the metastasized cancer is selected from bladder cancer, breast cancer, colon cancer, gastroenterological cancer, kidney cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, proximal or distal bile duct cancer, and melanoma. In some embodiments, the cancer is a colon cancer. In some embodiments, the colon cancer is adenocarcinoma, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors, primary colorectal lymphoma, leiomyosarcoma, melanoma, squamous cell-carcinoma, mucinous

adenocarcinoma, or Signet ring cell adenocarcinoma. In some embodiments, the cancer is a breast cancer. In some embodiments, the breast cancer is ductal carcinoma in situ, lobular carcinoma in situ, invasive or infiltrating ductal carcinoma, invasive or infiltrating lobular carcinoma, inflammatory breast cancer, triple-negative breast cancer, paget disease of the nipple, phyllodes tumor, angiosarcoma or invasive breast carcinoma. In some embodiments, the method further comprises administering an additional anticancer agent. In some embodiments, the additional anticancer agent is selected from among a chemotherapeutic agent, radiation therapy, immunotherapy, or a combination thereof. In some embodiments, the chemotherapeutic agent is selected from among chlorambucil, ifosfamide, doxorubicin, mesalazine, thalidomide, lenalidomide, temsirolimus, everolimus, fludarabine, fostamatinib, paclitaxel, docetaxel, ofatumumab, rituximab, dexamethasone, prednisone, CAL-101, ibritumomab, tositumomab, bortezomib, pentostatin, endostatin, or a combination thereof.

[0007] In some embodiments, a method of decreasing VEGF and/or decreasing

VEGF secretion is provided. The method comprises the steps of administering a Btk inhibitor and an immunomodulating agent to an individual in need thereof. In some embodiments, the Btk inhibitor is ibrutinib and the immunomodulating agent is a CTLA-4 inhibitor.

[0008] In some embodiments, a method of reducing, decreasing, and/or inhibiting angiogenesis is provided. The method comprises the steps of administering a Btk inhibitor and an immunomodulating agent to an individual in need thereof. In some embodiments, the Btk inhibitor is ibrutinib and the immunomodulating agent is a CTLA-4 inhibitor. BRIEF DESCRIPTION OF THE FIGURES

[0009] Figs. 1 A-E exemplify that ibrutinib enhanced the therapeutic efficacy of aCTLA-4 against the A20 B-cell lymphoma.

[0010] Figs. 2A-2G exemplify that ibrutinib enhanced the therapeutic efficacy of aCTLA-4 against the CT26 colon carcinoma.

[0011] Fig. 3 exemplifies that aCTLA-4 + ibrutinib generated a robust, tumor- specific immunologic memory.

[0012] Figs. 4A-4R exemplify that aCTLA-4 + ibrutinib increased tumor infiltration by Ki-67+/IFN-y+ CD4+and CD8+ T cells.

[0013] Fig. 5 is a schematic of the effect of ibrutinib on the T-cell activation pathway.

[0014] Figs. 6A-6E show the effect of ibrutinib, either alone or in combination with an immunomodulating agent, in the mouse MBT-bladder cancer model.

[0015] Fig. 7 shows the effect of ibrutinib, either alone or in combination with an immunomodulating agent, on survival in the mouse MBT-bladder cancer model.

[0016] Figs. 8A-E show the effect of ibrutinib, either alone or in combination with anti-PD-1 inhibitor, in the mouse MC38 colorectal tumor model.

[0017] Figs. 9A-9E show the effect of ibrutinib, either alone or in combination with anti-PD-Ll inhibitor, in the mouse MC38 colorectal tumor model.

[0018] Figs. 10A-E show the effect of ibrutinib, either alone or in combination with anti-CTLA-4 inhibitor, in the mouse MC38 colorectal tumor model.

DETAILED DESCRIPTION OF THE INVENTION

[0019] Small molecule Btk inhibitors, such as ibrutinib, are useful for reducing the risk of or treating a variety of diseases affected by or affecting many cell types of the hematopoietic lineage including, e.g., autoimmune diseases, heteroimmune conditions or diseases, inflammatory diseases, cancer (e.g., B-cell proliferative disorders), and

thromboembolic disorders.

[0020] Described herein, in certain embodiments, are methods, combinations, compositions, biomarkers, and kits for inducing tumor-specific immunological memory in a cancer, which comprises administration of a combination of a Btk inhibitor and an

immunomodulating agent. In some embodiments, described herein are methods,

combinations, compositions, biomarkers, and kits for inducing tumor-specific immunological memory in a cancer, which comprises administration of a combination of a Btk inhibitor and a CTLA-4 inhibitor. In some embodiments, described herein are methods, combinations, compositions, biomarkers, and kits for inducing tumor-specific immunological memory in a colon cancer, which comprises administration of a combination of a Btk inhibitor and an immunomodulating agent. In some embodiments, described herein are methods,

combinations, compositions, biomarkers, and kits for inducing tumor-specific immunological memory in a hematological malignancy, which comprises administration of a combination of a Btk inhibitor and an immunomodulating agent. In some embodiments, described herein are methods, combinations, compositions, biomarkers, and kits for inducing tumor-specific immunological memory in a hematological malignancy, which comprises administration of a combination of a Btk inhibitor and a CTLA-4 inhibitor.

Certain Terminology

[0021] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which the claimed subject matter belongs. It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any subject matter claimed. In this application, the use of the singular includes the plural unless specifically stated otherwise. It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise. In this application, the use of "or" means "and/or" unless stated otherwise. Furthermore, use of the term "including" as well as other forms, such as "include", "includes," and "included," is not limiting.

[0022] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited in the application including, but not limited to, patents, patent applications, articles, books, manuals, and treatises are hereby expressly incorporated by reference in their entirety for any purpose.

[0023] The term "acceptable" or "pharmaceutically acceptable", with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated or does not abrogate the biological activity or properties of the compound, and is relatively nontoxic.

[0024] "Bioavailability" refers to the percentage of ibrutinib dosed that is delivered into the general circulation of the animal or human being studied. The total exposure

(AUC(O-oo)) of a drug when administered intravenously is usually defined as 100% bioavailable (F%). "Oral bioavailability" refers to the extent to which ibrutinib is absorbed into the general circulation when the pharmaceutical composition is taken orally as compared to intravenous injection.

[0025] "Blood plasma concentration" refers to the concentration of ibrutinib in the plasma component of blood of a subject. It is understood that the plasma concentration of ibrutinib may vary significantly between subjects, due to variability with respect to metabolism and/or possible interactions with other therapeutic agents. In accordance with one embodiment disclosed herein, the blood or plasma concentration of ibrutinib may vary from subject to subject. Likewise, values such as maximum plasma concentration (Cmax) or time to reach maximum plasma concentration (Tmax), or total area under the plasma concentration time curve (AUC(O-co)) may vary from subject to subject. Due to this variability, the amount necessary to constitute "a therapeutically effective amount" of ibrutinib may vary from subject to subject.

[0026] The terms "co-administration" or the like, as used herein, are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time.

[0027] The terms "effective amount" or "therapeutically effective amount," as used herein, refer to a sufficient amount of an agent or a compound being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic uses is the amount of the composition including a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms without undue adverse side effects. An appropriate "effective amount" in any individual case may be determined using techniques, such as a dose escalation study. The term "therapeutically effective amount" includes, for example, a prophylactically effective amount. An "effective amount" of a compound disclosed herein is an amount effective to achieve a desired pharmacologic effect or therapeutic improvement without undue adverse side effects. It is understood that "an effect amount" or "a therapeutically effective amount" can vary from subject to subject, due to variation in metabolism of ibrutinib, age, weight, general condition of the subject, the condition being treated, the severity of the condition being treated, and the judgment of the prescribing physician. By way of example only, therapeutically effective amounts may be determined by routine experimentation, including but not limited to a dose escalation clinical trial.

[0028] The terms "enhance" or "enhancing" means to increase or prolong either in potency or duration a desired effect. By way of example, "enhancing" the effect of

therapeutic agents refers to the ability to increase or prolong, either in potency or duration, the effect of therapeutic agents on during treatment of a disease, disorder or condition. An "enhancing-effective amount," as used herein, refers to an amount adequate to enhance the effect of a therapeutic agent in inducing tumor-specific immunological memory in a disease, disorder or condition. When used in a patient, amounts effective for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician.

[0029] The terms "subject", "patient" and "individual" are used interchangeably. As used herein, they refer to an animal. By way of example only, a subject may be, but is not limited to, a mammal including, but not limited to, a human. The terms do not require the supervision (whether continuous or intermittent) of a medical professional.

[0030] The terms "treat," "treating" or "treatment", as used herein, include alleviating, abating or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting the disease or condition, e.g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by the disease or condition, or stopping the symptoms of the disease or condition. The terms "treat," "treating" or "treatment", include, but are not limited to, prophylactic and/or therapeutic treatments.

[0031] As used herein, the IC50 refers to an amount, concentration or dosage of a particular test compound that achieves a 50% inhibition of a maximal response, such as inhibition of Btk, in an assay that measures such response.

[0032] As used herein, EC50 refers to a dosage, concentration or amount of a particular test compound that elicits a dose-dependent response at 50% of maximal expression of a particular response that is induced, provoked or potentiated by the particular test compound.

[0033] As used herein, "cancer recurrence", "cancer relapse", "relapsed or refractory disease" are used interchangeably herein to refer to a return of cancer following treatment, and includes return of cancer in the primary organ, as well as distant recurrence, where the cancer returns outside of the primary organ. Btk Inhibitor Compounds Including Ibrutinib, and Pharmaceutically Acceptable Salts Thereof

[0034] The Btk inhibitor compound described herein (i.e. ibrutinib) is selective for

Btk and kinases having a cysteine residue in an amino acid sequence position of the tyrosine kinase that is homologous to the amino acid sequence position of cysteine 481 in Btk. The Btk inhibitor compound can form a covalent bond with Cys 481 of Btk (e.g., via a Michael reaction).

[0035] In some embodiments, the Btk inhibitor is a compound of Formula (A) having the structure:

Formula (A);

wherein:

A is N;

Ri is phenyl-O-phenyl or phenyl-S-phenyl;

R ₂ and R ₃ are independently H;

R4 is L ₃ -X-L ₄ -G, wherein,

L ₃ is optional, and when present is a bond, optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted cycloalkyl, optionally substituted or

unsubstituted alkenyl, optionally substituted or unsubstituted alkynyl;

X is optional, and when present is a bond, -0-, -C(=0)-, -S-, -S(=0)-, -S(=0) ₂ -, - H-, - R ₉ -, - HC(O)-, -C(0) H-, - R ₉ C(0)-, -C(0) R ₉ -, -S(=0) ₂ H-, - HS(=0) ₂ -, - S(=0) ₂ R ₉ -, -NR ₉ S(=0) ₂ -, -OC(0) H-, - HC(0)0-, -OC(0)NR ₉ -, - R ₉ C(0)0-, -CH=NO-, -ON=CH-, - RioC(0)NRio-, heteroaryl-, aryl-, -

L ₄ is optional, and when present is a bond, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle;

or L ₃ , X and L ₄ taken together form a nitrogen containing heterocyclic ring;

R6, R-7 and R ₈ are independently selected from among H, halogen, CN, OH, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl or substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;

each R ₉ is independently selected from among H, substituted or unsubstituted lower alkyl, and substituted or unsubstituted lower cycloalkyl;

each Rio is independently H, substituted or unsubstituted lower alkyl, or substituted or unsubstituted lower cycloalkyl; or

two Rio groups can together form a 5-, 6-, 7-, or 8-membered heterocyclic ring; or

Rio and Rn can together form a 5-, 6-, 7-, or 8-membered heterocyclic ring; or each Rii is independently selected from H or substituted or unsubstituted alkyl; or a

pharmaceutically acceptable salt thereof. In some embodiments, L ₃ , X and L ₄ taken together form a nitrogen containing heterocyclic ring. In some embodiments, the nitrogen containing

heterocyclic ring is a piperidine group. In some embodiments, G is

. In some embodiments, the compound of Formula (A) is l-[(3R)-3-[4-amino-3-

(4-phenoxyphenyl)pyrazolo[3 ,4-d]pyrimidin- 1 -yljpiperidin- 1 -yl]prop-2-en- 1 -one.

[0036] "Ibrutinib" or "l-((R)-3-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4- d]pyrimidin- 1 -yl)piperidin- 1 -yl)prop-2-en- 1 -one" or " 1 - { (3R)-3 -[4-amino-3 -(4- phenoxyphenyl)- lH-pyrazolo[3 ,4-<i]pyrimidin- 1 -yljpiperidin- 1 -yl }prop-2-en- 1 -one" or "2- Propen- 1 -one, 1 -[(3R)-3 -[4-amino-3 -(4-phenoxyphenyl)- lH-pyrazolo[3 ,4-<i]pyrimidin- 1 -yl]- 1-piperidinyl-" or ibrutinib or any other suitable name refers to the compound with the following structure:

A wide variety of pharmaceutically acceptable salts is formed from ibrutinib and includes:

- acid addition salts formed by reacting ibrutinib with an organic acid, which includes aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyl alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, amino acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like;

- acid addition salts formed by reacting ibrutinib with an inorganic acid, which includes hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like.

[0037] The term "pharmaceutically acceptable salts" in reference to ibrutinib refers to a salt of Ibrutinib, which does not cause significant irritation to a mammal to which it is administered and does not substantially abrogate the biological activity and properties of the compound.

[0038] It should be understood that a reference to a pharmaceutically acceptable salt includes the solvent addition forms (solvates). Solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are formed during the process of product formation or isolation with pharmaceutically acceptable solvents such as water, ethanol, methanol, methyl tert-butyl ether (MTBE), diisopropyl ether (DIPE), ethyl acetate, isopropyl acetate, isopropyl alcohol, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), acetone, nitromethane, tetrahydrofuran (THF), dichloromethane (DCM), dioxane, heptanes, toluene, anisole, acetonitrile, and the like. In one aspect, solvates are formed using, but limited to, Class 3 solvent(s). Categories of solvents are defined in, for example, the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), "Impurities: Guidelines for Residual Solvents, Q3C(R3), (November 2005). Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. In some embodiments, solvates of ibrutinib, or pharmaceutically acceptable salts thereof, are conveniently prepared or formed during the processes described herein. In some embodiments, solvates of ibrutinib are anhydrous. In some embodiments, ibrutinib, or pharmaceutically acceptable salts thereof, exist in unsolvated form. In some embodiments, ibrutinib, or pharmaceutically acceptable salts thereof, exist in unsolvated form and are anhydrous.

[0039] In yet other embodiments, ibrutinib, or a pharmaceutically acceptable salt thereof, is prepared in various forms, including but not limited to, amorphous phase, crystalline forms, milled forms and nano-particulate forms. In some embodiments, ibrutinib, or a pharmaceutically acceptable salt thereof, is amorphous. In some embodiments, ibrutinib, or a pharmaceutically acceptable salt thereof, is amorphous and anhydrous. In some embodiments, ibrutinib, or a pharmaceutically acceptable salt thereof, is crystalline. In some embodiments, ibrutinib, or a pharmaceutically acceptable salt thereof, is crystalline and anhydrous.

[0040] In some embodiments, ibrutinib is prepared as outlined in U.S. Patent No.

7,514,444.

[0041] In some embodiments, the Btk inhibitor is ibrutinib (PCI-32765), PCI-45292,

PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA- 056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono

Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), HM71224 (Hanmi Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-0853 (Genentech), or combinations thereof.

[0042] In some embodiments, the Btk inhibitor is 4-(tert-butyl)-N-(2-methyl-3-(4- methyl-6-((4-(morpholine-4-carbonyl)phenyl)amino)-5-oxo-4,5- dihydropyrazin-2- yl)phenyl)benzamide (CGI-1746); 7-benzyl-l-(3-(piperidin-l-yl)propyl)-2-(4-(pyridin-4- yl)phenyl)-lH-imidazo[4,5-g]quinoxalin-6(5H)-one (CTA-056); (R)-N-(3-(6-(4-(l,4- dimethyl-3-oxopiperazin-2-yl)phenylamino)-4-methyl-5-oxo-4,5 -dihydropyrazin-2-yl)-2- methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxam ide (GDC-0834); 6- cyclopropyl-8-fluoro-2-(2-hydroxymethyl-3-{ l-methyl-5-[5-(4-methyl-piperazin-l-yl)- pyridin-2-ylamino]-6-oxo-l,6-dihydro-pyridin-3-yl}-phenyl)-2 H-isoquinolin-l-one (RN-486); N-[5-[5-(4-acetylpiperazine-l-carbonyl)-4-methoxy-2-methylph enyl]sulfanyl-l,3-thiazol-2- yl]-4-[(3,3-dimethylbutan-2-ylamino)methyl]benzamide (BMS-509744, HY-11092); or N-(5- ((5-(4-Acetylpiperazine-l-carbonyl)-4-methoxy-2-methylphenyl )thio)thiazol-2-yl)-4-(((3- methylbutan-2-yl)amino)methyl)benzamide (HY11066); or a pharmaceutically acceptable salt thereof.

[0043 In some embodiments, the Btk inhibitor is:

; or a pharmaceutically acceptable salt thereof.

Additional TEC Family Kinase Inhibitors

[0044] BTK is a member of the Tyrosine-protein kinase (TEC) family of kinases. In some embodiments, the TEC family comprises BTK, ITK, TEC, RLK and BMX. In some embodiments, a TEC family kinase inhibitor inhibits the kinase activity of BTK, ITK, TEC, RLK and BMX. In some embodiments, a TEC family kinase inhibitor is a BTK inhibitor, which is disclosed elsewhere herein. In some embodiments, a TEC family kinase inhibitor is an ITK inhibitor. In some embodiments, a TEC family kinase inhibitor is a TEC inhibitor. In some embodiments, a TEC family kinase inhibitor is a RLK inhibitor. In some embodiments, a TEC family kinase inhibitor is a BMK inhibitor.

[0045] In some embodiments, the Itk inhibitor covalently binds to Cysteine 442 of

ITK. In some embodiments, the Itk inhibitor is an Itk inhibitor compound described in WO2002/0500071, which is incorporated by reference in its entirety. In some embodiments, the Itk inhibitor is an Itk inhibitor compound described in WO2005/070420, which is incorporated by reference in its entirety. In some embodiments, the Itk inhibitor is an Itk inhibitor compound described in WO2005/079791, which is incorporated by reference in its entirety. In some embodiments, the Itk inhibitor is an Itk inhibitor compound described in WO2007/076228, which is incorporated by reference in its entirety. In some embodiments, the Itk inhibitor is an Itk inhibitor compound described in WO2007/058832, which is incorporated by reference in its entirety. In some embodiments, the Itk inhibitor is an Itk inhibitor compound described in WO2004/016610, which is incorporated by reference in its entirety. In some embodiments, the Itk inhibitor is an Itk inhibitor compound described in WO2004/016611, which is incorporated by reference in its entirety. In some embodiments, the Itk inhibitor is an Itk inhibitor compound described in WO2004/016600, which is incorporated by reference in its entirety. In some embodiments, the Itk inhibitor is an Itk inhibitor compound described in WO2004/016615, which is incorporated by reference in its entirety. In some embodiments, the Itk inhibitor is an Itk inhibitor compound described in WO2005/026175, which is incorporated by reference in its entirety. In some embodiments, the Itk inhibitor is an Itk inhibitor compound described in WO2006/065946, which is incorporated by reference in its entirety. In some embodiments, the Itk inhibitor is an Itk inhibitor compound described in WO2007/027594, which is incorporated by reference in its entirety. In some embodiments, the Itk inhibitor is an Itk inhibitor compound described in WO2007/017455, which is incorporated by reference in its entirety. In some embodiments, the Itk inhibitor is an Itk inhibitor compound described in WO2008/025820, which is incorporated by reference in its entirety. In some embodiments, the Itk inhibitor is an Itk inhibitor compound described in WO2008/025821, which is incorporated by reference in its entirety. In some embodiments, the Itk inhibitor is an Itk inhibitor compound described in WO2008/025822, which is incorporated by reference in its entirety. In some embodiments, the Itk inhibitor is an Itk inhibitor compound described in WO2011/017219, which is incorporated by reference in its entirety. In some embodiments, the Itk inhibitor is an Itk inhibitor compound described in WO2011/090760, which is incorporated by reference in its entirety. In some embodiments, the Itk inhibitor is an Itk inhibitor compound described in WO2009/158571, which is incorporated by reference in its entirety. In some embodiments, the Itk inhibitor is an Itk inhibitor compound described in WO2009/051822, which is incorporated by reference in its entirety. In some embodiments, the Itk inhibitor is an Itk inhibitor compound described in US 13/177657, which is incorporated by reference in its entirety.

[0046] In some embodiments, the Itk inhibitor has a structure selected from:

Combination with Immunomodulating Agent

[0047] Disclosed herein, in certain embodiments, are pharmaceutical combinations which comprise a TEC inhibitor and an immunotherapeutic agent. In some embodiments, the TEC inhibitor is a BTK, ITK, TEC, RLK, or BMX inhibitor. In some embodiments, the TEC inhibitor is a BTK inhibitor or an ITK inhibitor. In some embodiments, the TEC inhibitor is a BTK inhibitor. In some embodiments, the Btk inhibitor is ibrutinib. In some embodiments, the immunotherapeutic agent is an immunomodulating agent.

[0048] As used herein, the term "immunomodulating molecules" refers to a group of molecules on the cell surface of CD4 and CD8 T cells. In some embodiments, these molecules are activators of T cells. In some embodiments, these molecules effectively serve as "brakes" to down-modulate or inhibit an anti-tumor immune response. Immunomodulating molecules include, but are not limited to, Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof.

[0049] "Immunomodulating agents," as used herein refer to any agent that modulates the activity of T cell cell-surface co-inhibitory or co-stimulatory activity. Immunomodulating agents include small molecule inhibitors, antibodies, antibody-derivatives (including Fab fragments and scFvs), antibody-drug conjugates, antisense oligonucleotides, siRNA, aptamers, peptides and peptide mimetics. Inhibitory nucleic acids that decrease the expression and/or activity of immune checkpoint molecules can also be used in the methods disclosed herein. One embodiment is a small inhibitory RNA (siRNA) for interference or inhibition of expression of a target gene. Nucleic acid sequences encoding PD-1, PD-Ll and PD-L2 are disclosed in GENBANK® Accession Nos. NM— 005018, AF344424, NP— 079515, and NP— 054862.

[0050] As described elsewhere herein, in some instances a Btk inhibitor (e.g., ibrutinib) and an immunomodulating agent are co-administered concurrently (e.g., simultaneously, essentially simultaneously or within the same treatment protocol) or sequentially.

[0051] In some embodiments, a Btk inhibitor (e.g., ibrutinib) and an

immunomodulating agent are co-administered in separate dosage forms. In some

embodiments, ibrutinib and an immunomodulating agent are co-administered in combined dosage forms.

[0052] In some embodiments, a Btk inhibitor (e.g., ibrutinib) and an

immunomodulating agent are administered in separate dosage forms and on separate dosing schedules. In some embodiments, the Btk inhibitor (e.g., ibrutinib) is administered once per day and the immunomodulating agent (e.g., a CTLA-4 inhibitor) is administered once every two days.

[0053] In some embodiments, the Btk inhibitor (e.g., ibrutinib), functions to suppress the Thl response while enhancing the Th2 response. In some embodiments, ibrutinib functions to decrease the number of Th2 polarized T cells in a subject. In some embodiments, ibrutinib functions to increase the number of Thl polarized T cells in a subject. In some embodiments, ibrutinib functions to increase the number of activated CD8+ cytotoxic T cells in a subject. In some embodiments, ibrutinib functions to increase the ratio of Thl polarized T cells to Th2 polarized T cells in a subject. In some embodiments, ibrutinib functions to increase IFN-γ expression in a subject.

[0054] In some embodiments, the co-administration of a Btk inhibitor (e.g., ibrutinib) and an immunomodulating agent increases the oral bioavailability of ibrutinib. In some embodiments, the co-administration of ibrutinib and an immunomodulating agent increases the Cmax of ibrutinib. In some embodiments, the co-administration of ibrutinib and an immunomodulating agent increases the AUC of ibrutinib.

In some embodiments, co-administration of a Btk inhibitor (e.g., ibrutinib) and an

immunomodulating agent does not significantly affect the Tmax or Tl/2 of ibrutinib as compared to the Tmax and Tl/2 of ibrutinib administered without an immunomodulating agent.

[0055] In some embodiments, the daily dosage of a Btk inhibitor (e.g., ibrutinib) when administered in combination with an immunomodulating agent is about 10 mg to about 1000 mg. In some embodiments, the daily dosage of ibrutinib when administered in combination with an immunomodulating agent is about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 1 10 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 420 mg, about 450 mg, about 500 mg, about 550 mg, about 560 mg, about 600 mg, about 700 mg, 800 mg, or about 840 mg. In some embodiments, the daily dosage of ibrutinib when administered in combination with an immunomodulating agent is about 40 mg to about 140 mg. In some embodiments, the daily dosage of ibrutinib when administered in combination with an immunomodulating agent is about 40 mg to about 100 mg. In some embodiments, the daily dosage of ibrutinib when administered in combination with an immunomodulating agent is about 40 mg to about 70 mg. In some embodiments, the daily dosage of ibrutinib when administered in combination with an immunomodulating agent is about 40 mg.

[0056] Any suitable daily dose of an immunomodulating agent is contemplated for use with the compositions, dosage forms, and methods disclosed herein. Daily dose of the immunomodulating agent depends on multiple factors, the determination of which is within the skills of one of skill in the art. For example, the daily dose of the immunomodulating agent depends of the strength of the immunomodulating agent. Weak immunomodulating agents will require higher daily doses than moderate immunomodulating agents, and moderate immunomodulating agents will require higher daily doses than strong

immunomodulating agents.

Exemplary Immunomodulating Agents

[0057] In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments the

immunomodulating agent is an inhibitory antibody that binds a co-inhibitory molecule or its natural ligand as set forth in Table 1.

TABLE 1. Co-inhibitory molecules on T cells, NK cells

[0058] In some embodiments the immunomodulating agent is an activating antibody that binds a co-stimulatory molecule or its natural ligand as set forth in Table 2. TABLE 2. Co-stimulatory molecules on T cells, NK cells

[0059] In some embodiments, a TEC inhibitor is co-administered with an

immunomodulating agent, wherein the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the

immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TEVI3. In some embodiments, the TEC inhibitor is a Btk inhibitor or an Itk inhibitor. In some embodiments, the TEC inhibitor is a Btk inhibitor. In some

embodiments, the TEC inhibitor is an Itk inhibitor.

[0060] In some embodiments, the Itk inhibitor is co-administered with an

immunomodulating agent, wherein the immunomodulating agent is an inhibitor of

Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3.

[0061] In some embodiments, the Btk inhibitor is co-administered with an

immunomodulating agent, wherein the immunomodulating agent is an inhibitor of

Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some

embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the

immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the

immunomodulating agent is an inhibitor of LAG3. In some embodiments, the

immunomodulating agent is an inhibitor of TIM3. In some embodiments, the

immunomodulating agent is an antibody. In some embodiments, the immunomodulating agent is a monoclonal antibody. In some embodiments, the Btk inhibitor is ibrutinib.

[0062] In some embodiments, ibrutinib is co-administered with an

immunomodulating agent, wherein the immunomodulating agent is an inhibitor of

Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some

embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the

immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the

immunomodulating agent is an inhibitor of LAG3. In some embodiments, the

immunomodulating agent is an inhibitor of TIM3. In some embodiments, the

immunomodulating agent is an antibody. In some embodiments, the immunomodulating agent is a monoclonal antibody.

[0063] Any suitable immunomodulating agent is contemplated for use with the compositions, dosage forms, and methods disclosed herein. The selection of the

immunomodulating agent depends on multiple factors, and the selection of the

immunomodulating agent is within the skills of one of skill in the art. For example, factors to be considered include the desired reduction in the daily dose of ibrutinib, any additional drug interactions of the immunomodulating agent, and the length for which the

immunomodulating agent may be taken. In certain instances, the immunomodulating agent is an immunomodulating agent which may be taken long-term, for example chronically.

Immunomodulating agents, as referred to herein, refers to any agent that inhibits the immune checkpoint blockade signal that the immune checkpoint molecule in question regulates.

Immunomodulating agents can include, but are not limited to, immune checkpoint molecule binding proteins, antibodies (or fragments or variants thereof) that bind to immune checkpoint molecules, nucleic acids that downregulate expression of the immune checkpoint molecules, or any other molecules that bind to immune checkpoint molecules (i.e. small organic molecules, peptidomimetics, aptamers, etc.).

[0064] In some embodiments, the immunomodulating agent is an antibody. The antibodies for use in the present invention include, but are not limited to, monoclonal antibodies, synthetic antibodies, polyclonal antibodies, multispecific antibodies (including bi- specific antibodies), human antibodies, humanized antibodies, chimeric antibodies, single- chain Fvs (scFv) (including bi-specific scFvs), single chain antibodies, Fab fragments, F(ab') fragments, disulfide-linked Fvs (sdFv), and epitope-binding fragments of any of the above. In particular, antibodies for use in the present invention include immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, i.e., molecules that contain a binding site for an immune checkpoint molecule that immunospecifically bind to the immune checkpoint molecule. The immunoglobulin molecules for use in the invention can be of any type {e.g., IgG, IgE, IgM, IgD, IgA and IgY), class {e.g., IgGl, IgG2, IgG3, IgG4, IgAl and IgA2) or subclass of immunoglobulin molecule. Preferably, the antibodies for use in the invention are IgG, more preferably, IgGl.

[0065] An antibody against an immune checkpoint molecule suitable for use with the methods disclosed herein may be from any animal origin including birds and mammals (e.g., human, murine, donkey, sheep, rabbit, goat, guinea pig, camel, horse, shark or chicken). Preferably, the antibodies are human or humanized monoclonal antibodies. As used herein, "human" antibodies include antibodies having the amino acid sequence of a human immunoglobulin and include antibodies isolated from human immunoglobulin libraries or from mice or other animals that express antibodies from human genes.

[0066] An antibody against an immune checkpoint molecule suitable for use with the methods disclosed herein may be monospecific, bispecific, trispecific or of greater multispecificity. Multispecific antibodies may immunospecifically bind to different epitopes of a polypeptide or may immunospecifically bind to both a polypeptide as well as a heterologous epitope, such as a heterologous polypeptide or solid support material.

PD-Ll Inhibitors

[0067] In some embodiments, the immunomodulating agent is an inhibitor of PD-Ll .

In some embodiments, the immunomodulating agent is an antibody against PD-Ll . In some embodiments, the immunomodulating agent is a monoclonal antibody against PD-Ll . In other or additional embodiments, the immunomodulating agent is a human or humanized antibody against PD-Ll . In one embodiment, the immunomodulating agent reduces the expression or activity of one or more immune checkpoint proteins, such as PD-Ll . In another embodiment, the immunomodulating agent reduces the interaction between PD-1 and PD-Ll . Exemplary immunomodulating agents include antibodies (e.g., an anti-PD-Ll antibody), RNAi molecules (e.g., anti-PD-Ll RNAi), antisense molecules (e.g., an anti-PD-Ll antisense RNA), dominant negative proteins (e.g., a dominant negative PD-Ll protein), and small molecule inhibitors. Antibodies include monoclonal antibodies, humanized antibodies, deimmunized antibodies, and Ig fusion proteins. An exemplary anti-PD-Ll antibody includes clone EH12. Exemplary antibodies against PD-Ll include: Genentech's MPDL3280A (RG7446); Anti-mouse PD-Ll antibody Clone 10F.9G2 (Cat # BE0101) from BioXcell; anti- PD-Ll monoclonal antibody MDX-1105 (BMS-936559) and BMS-935559 from Bristol- Meyer's Squibb; MSB0010718C; mouse anti-PD-Ll Clone 29E.2A3; and AstraZeneca's MEDI4736. In some embodiments, the anti-PD-Ll antibody is an anti-PD-Ll antibody disclosed in any of the following patent publications (herein incorporated by reference): WO2013079174; CN101104640; WO2010036959; WO2013056716; WO2007005874; WO2010089411; WO2010077634; WO2004004771; WO2006133396; WO201309906; US 20140294898; WO2013181634 or WO2012145493.

[0068] In some embodiments, the PD-Ll inhibitor is a nucleic acid inhibitor of PD-

Ll expression. In some embodiments, the PD-Ll inhibitor is disclosed in one of the following patent publications (incorporated herein by reference): WO2011127180 or WO2011000841. In some embodiments, the PD-Ll inhibitor is rapamycin.

[0069] In some embodiments, a TEC inhibitor is administered in combination with a

PD-Ll inhibitor described above and elsewhere for inducing tumor-specific immunological memory in a cancer. In some embodiments, the TEC inhibitor is a Btk inhibitor or an Itk inhibitor. In some embodiments, the TEC inhibitor is a Btk inhibitor. In some embodiments, the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila

Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene

Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene Corporation), AVL-291/CC- 291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI

Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA-056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486

(Hoffmann-La Roche), HM71224 (Hanmi Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-0853 (Genentech), or combinations thereof. In some embodiments, the Btk inhibitor is ibrutinib.

[0070] In some embodiments, a Btk inhibitor is administered in combination with a

PD-Ll inhibitor for inducing tumor-specific immunological memory in a cancer. In some embodiments, the PD-Ll inhibitor is selected from Genentech's MPDL3280A (RG7446); Anti-mouse PD-Ll antibody Clone 10F.9G2 (Cat # BE0101) from BioXcell; anti-PD-Ll monoclonal antibody MDX-1105 (BMS-936559) and BMS-935559 from Bristol -Meyer's Squibb; MSB0010718C; mouse anti-PD-Ll Clone 29E.2A3; AstraZeneca's MEDI4736; EH12; and rapamycin. In some embodiments, a Btk inhibitor is administered in combination with a PD-Ll inhibitor selected from Genentech's MPDL3280A (RG7446); Anti-mouse PD- Ll antibody Clone 10F.9G2 (Cat # BE0101) from BioXcell; anti-PD-Ll monoclonal antibody MDX-1105 (BMS-936559) and BMS-935559 from Bristol-Meyer's Squibb; MSB0010718C; mouse anti-PD-Ll Clone 29E.2A3; AstraZeneca's MEDI4736; EH12; and rapamycin for inducing tumor-specific immunological memory in a cancer.

[0071] In some embodiments, ibrutinib is administered in combination with a PD-L1 inhibitor for inducing tumor-specific immunological memory in a cancer. In some

embodiments, the PD-L1 inhibitor is selected from Genentech's MPDL3280A (RG7446); Anti-mouse PD-L1 antibody Clone 10F.9G2 (Cat # BE0101) from BioXcell; anti-PD-Ll monoclonal antibody MDX-1105 (BMS-936559) and BMS-935559 from Bristol -Meyer's Squibb; MSB0010718C; mouse anti-PD-Ll Clone 29E.2A3; AstraZeneca's MEDI4736;

EH12; and rapamycin. In some embodiments, ibrutinib is administered in combination with a PD-L1 inhibitor selected from Genentech's MPDL3280A (RG7446); Anti-mouse PD-L1 antibody Clone 10F.9G2 (Cat # BE0101) from BioXcell; anti-PD-Ll monoclonal antibody MDX-1105 (BMS-936559) and BMS-935559 from Bristol-Meyer's Squibb; MSB0010718C; mouse anti-PD-Ll Clone 29E.2A3; AstraZeneca's MEDI4736; EH12; and rapamycin for inducing tumor-specific immunological memory in a cancer.

PD-L2 Inhibitors

[0072] In some embodiments, the immunomodulating agent is an inhibitor of PD-L2.

In some embodiments, the immunomodulating agent is an antibody against PD-L2. In some embodiments, the immunomodulating agent is a monoclonal antibody against PD-L2. In other or additional embodiments, the immunomodulating agent is a human or humanized antibody against PD-L2. In some embodiments, the immunomodulating agent reduces the expression or activity of one or more immune checkpoint proteins, such as PD-L2. In other embodiments, the immunomodulating agent reduces the interaction between PD-1 and PD-L2. Exemplary immunomodulating agents include antibodies (e.g., an anti-PD-L2 antibody), RNAi molecules (e.g., an anti-PD-L2 RNAi), antisense molecules (e.g., an anti-PD-L2 antisense RNA), dominant negative proteins (e.g., a dominant negative PD-L2 protein), and small molecule inhibitors. Antibodies include monoclonal antibodies, humanized antibodies, deimmunized antibodies, and Ig fusion proteins.

[0073] In some embodiments, the PD-L2 inhibitor is GlaxoSmithKline's AMP-224

(Amplimmune). In some embodiments, the PD-L2 inhibitor is rHIgM12B7.

[0074] In some embodiments, a TEC inhibitor is administered in combination with a

PD-L2 inhibitor described above and elsewhere for inducing tumor-specific immunological memory in a cancer. In some embodiments, the TEC inhibitor is a Btk inhibitor or an Itk inhibitor. In some embodiments, the TEC inhibitor is a Btk inhibitor. In some embodiments, the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene

Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene Corporation), AVL-291/CC- 291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI

Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA-056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486

(Hoffmann-La Roche), HM71224 (Hanmi Pharmaceutical Company Limited),LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-0853 (Genentech), or combinations thereof. In some embodiments, the Btk inhibitor is ibrutinib.

[0075] In some embodiments, a Btk inhibitor is administered in combination with a

PD-L2 inhibitor for inducing tumor-specific immunological memory in cancer. In some embodiments, the PD-L2 inhibitor is selected from GlaxoSmithKline's AMP-224

(Amplimmune) and rHIgM12B7. In some embodiments, a BTK inhibitor is administered in combination with a PD-L2 inhibitor selected from GlaxoSmithKline's AMP-224

(Amplimmune) and rHIgM12B7 for inducing tumor-specific immunological memory in a cancer.

[0076] In some embodiments, ibrutinib is administered in combination with a PD-L2 inhibitor for inducing tumor-specific immunological memory in cancer. In some

embodiments, the PD-L2 inhibitor is selected from GlaxoSmithKline's AMP-224

(Amplimmune) and rHIgM12B7. In some embodiments, ibrutinib is administered in combination with a PD-L2 inhibitor selected from GlaxoSmithKline's AMP-224

(Amplimmune) and rHIgM12B7 for inducing tumor-specific immunological memory in a cancer.

PD-1 Inhibitors

[0077] In some embodiments, the immunomodulating agent is an inhibitor of PD-1.

In some embodiments, the immunomodulating agent is an antibody against PD-1. In some embodiments, the immunomodulating agent is a monoclonal antibody against PD-1. In other or additional embodiments, the immunomodulating agent is a human or humanized antibody against PD-1. For example, the inhibitors of PD-1 biological activity (or its ligands) disclosed in U.S. Pat. Nos. 7,029,674; 6,808,710; or U.S. Patent Application Nos: 20050250106 and 20050159351 can be used in the methods provided herein. Exemplary antibodies against PD- 1 include: Anti-mouse PD-1 antibody Clone J43 (Cat # BE0033-2) from BioXcell; Anti- mouse PD-1 antibody Clone RMP1-14 (Cat # BE0146) from BioXcell; mouse anti-PD-1 antibody Clone EH12; Merck's MK-3475 anti-mouse PD-1 antibody (Keytruda,

pembrolizumab, lambrolizumab); and AnaptysBio's anti-PD-1 antibody, known as ANBOl 1; antibody MDX-1 106 (ONO-4538); Bristol-Myers Squibb's human IgG4 monoclonal antibody nivolumab (Opdivo®, BMS-936558, MDX1106); AstraZeneca' s AMP-514, and AMP-224; and Pidilizumab (CT-011), CureTech Ltd.

[0078] Additional exemplary anti-PD-1 antibodies and methods for their use are described by Goldberg et al, Blood 1 10(1): 186-192 (2007), Thompson et al, Clin. Cancer Res. 13(6): 1757- 1761 (2007), and Korman et al, International Application No.

PCT/JP2006/309606 (publication no. WO 2006/121168 Al), each of which are expressly incorporated by reference herein. In some embodiments, the anti-PD-1 antibody is an anti- PD-1 antibody disclosed in any of the following patent publications (herein incorporated by reference): WO014557; WO2011110604; WO2008156712; US2012023752;

WO2011110621; WO2004072286; WO2004056875; WO20100036959; WO2010029434; WO201213548; WO2002078731; WO2012145493; WO2010089411; WO2001014557; WO2013022091 ; WO2013019906; WO2003011911; US20140294898; and WO2010001617.

[0079] In some embodiments, the PD-1 inhibitor is a PD-1 binding protein as disclosed in WO200914335 (herein incorporated by reference).

[0080] In some embodiments, the PD-1 inhibitor is a peptidomimetic inhibitor of PD-

1 as disclosed in WO2013132317 (herein incorporated by reference).

[0081] In some embodiments, the PD-1 inhibitor is a PD-L1 protein, a PD-L2 protein, or fragments, as well as antibody MDX-1 106 (ONO-4538) tested in clinical studies for inducing tumor-specific immunological memory in certain malignancies (Brahmer et al., J Clin Oncol. 2010 28(19): 3167-75, Epub 2010 Jun 1). Other blocking antibodies may be readily identified and prepared by the skilled person based on the known domain of interaction between PD-1 and PD-L1/PD-L2, as discussed above. For example, a peptide corresponding to the IgV region of PD-1 or PD-L1/PD-L2 (or to a portion of this region) could be used as an antigen to develop blocking antibodies using methods well known in the art.

[0082] In some embodiments, a TEC inhibitor is administered in combination with a

PD-1 inhibitor described above and elsewhere for inducing tumor-specific immunological memory in a cancer. In some embodiments, the TEC inhibitor is a Btk inhibitor or an Itk inhibitor. In some embodiments, the TEC inhibitor is a Btk inhibitor. In some embodiments, the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene

Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene Corporation), AVL-291/CC- 291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI

Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA-056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486

(Hoffmann-La Roche), HM71224 (Hanmi Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-0853 (Genentech), or combinations thereof. In some embodiments, the Btk inhibitor is ibrutinib.

[0083] In some embodiments, a Btk inhibitor is administered in combination with a

PD-1 inhibitor for inducing tumor-specific immunological memory in a cancer. In some embodiments, the PD-1 inhibitor is selected from anti-mouse PD-1 antibody Clone J43 (Cat # BE0033-2) from BioXcell; Anti-mouse PD-1 antibody Clone RMPl-14 (Cat # BE0146) from BioXcell; mouse anti-PD-1 antibody Clone EH12; Merck's MK-3475 anti-mouse PD-1 antibody (Keytruda, pembrolizumab, lambrolizumab); and AnaptysBio's anti-PD-1 antibody, known as ANB011; antibody MDX-1 106 (ONO-4538); Bristol-Myers Squibb's human IgG4 monoclonal antibody nivolumab (Opdivo®, BMS-936558, MDX1106); AstraZeneca's AMP- 514 and AMP-224; Pidilizumab (CT-011), CureTech Ltd; MDX-1 106 (ONO-4538); PD-L1; and PD-L2. In some embodiments, a Btk inhibitor is administered in combination with a PD- 1 inhibitor selected from anti-mouse PD-1 antibody Clone J43 (Cat # BE0033-2) from

BioXcell; Anti-mouse PD-1 antibody Clone RMPl-14 (Cat # BE0146) from BioXcell; mouse anti-PD-1 antibody Clone EH12; Merck's MK-3475 anti-mouse PD-1 antibody (Keytruda, pembrolizumab, lambrolizumab); and AnaptysBio's anti-PD-1 antibody, known as ANB011; antibody MDX-1 106 (ONO-4538); Bristol-Myers Squibb's human IgG4 monoclonal antibody nivolumab (Opdivo®, BMS-936558, MDX1106); AstraZeneca's AMP-514 and AMP-224; Pidilizumab (CT-011), CureTech Ltd; MDX-1 106 (ONO-4538); PD-L1; and PD- L2 for inducing tumor-specific immunological memory in a cancer.

[0084] In some embodiments, ibrutinib is administered in combination with a PD-1 inhibitor for inducing tumor-specific immunological memory in a cancer. In some

embodiments, the PD-1 inhibitor is selected from anti-mouse PD-1 antibody Clone J43 (Cat # BE0033-2) from BioXcell; Anti-mouse PD-1 antibody Clone RMPl-14 (Cat # BE0146) from BioXcell; mouse anti-PD-1 antibody Clone EH12; Merck's MK-3475 anti-mouse PD-1 antibody (Keytruda, pembrolizumab, lambrolizumab); and AnaptysBio's anti-PD-1 antibody, known as ANBOl 1; antibody MDX-1 106 (ONO-4538); Bristol-Myers Squibb's human IgG4 monoclonal antibody nivolumab (Opdivo®, BMS-936558, MDX1106); AstraZeneca's AMP- 514 and AMP-224; Pidilizumab (CT-011), CureTech Ltd; MDX-1 106 (ONO-4538); PD-L1; and PD-L2. In some embodiments, ibrutinib is administered in combination with a PD-1 inhibitor selected from anti-mouse PD-1 antibody Clone J43 (Cat # BE0033-2) from

BioXcell; Anti-mouse PD-1 antibody Clone RMPl-14 (Cat # BE0146) from BioXcell; mouse anti-PD-1 antibody Clone EH12; Merck's MK-3475 anti-mouse PD-1 antibody (Keytruda, pembrolizumab, lambrolizumab); and AnaptysBio's anti-PD-1 antibody, known as ANBOl 1; antibody MDX-1 106 (ONO-4538); Bristol-Myers Squibb's human IgG4 monoclonal antibody nivolumab (Opdivo®, BMS-936558, MDX1106); AstraZeneca's AMP-514 and AMP-224; Pidilizumab (CT-011), CureTech Ltd; MDX-1 106 (ONO-4538); PD-L1; and PD- L2 for inducing tumor-specific immunological memory in a cancer.

CTLA-4 Inhibitors

[0085] In some embodiments, the immunomodulating agent is an inhibitor of CTLA-

4. In some embodiments, the immunomodulating agent is an antibody against CTLA-4. In some embodiments, the immunomodulating agent is a monoclonal antibody against CTLA-4. In other or additional embodiments, the immunomodulating agent is a human or humanized antibody against CTLA-4. In one embodiment, the anti-CTLA-4 antibody blocks the binding of CTLA-4 to CD80 (B7-1) and/or CD86 (B7-2) expressed on antigen presenting cells.

Exemplary antibodies against CTLA-4 include: Bristol Meyers Squibb's anti-CTLA-4 antibody ipilimumab (also known as Yervoy®, MDX-010, BMS-734016 and MDX-101); anti-CTLA4 Antibody, clone 9H10 from Millipore; Pfizer' s tremelimumab (CP-675,206, ticilimumab); and anti-CTLA4 antibody clone BNI3 from Abeam.

[0086] In some embodiments, the anti-CTLA-4 antibody is an anti-CTLA-4 antibody disclosed in any of the following patent publications (herein incorporated by reference) :WO 2001014424; WO 2004035607; US2005/0201994; EP 1212422 B 1; WO2003086459;

WO2012120125; WO2000037504; WO2009100140; WO200609649; WO2005092380;

WO2007123737; WO2006029219; WO20100979597; WO200612168; and WO1997020574 . Additional CTLA-4 antibodies are described in U.S. Patent Nos. 5,811,097, 5,855,887, 6,051,227, and 6,984,720; in PCT Publication Nos. WO 01/14424 and WO 00/37504; and in U.S. Publication Nos. 2002/0039581 and 2002/086014; and/or U.S. Patent Nos. 5,977,318, 6,682,736, 7, 109,003, and 7, 132,281, incorporated herein by reference). In some

embodiments, the anti-CTLA-4 antibody is an, for example, those disclosed in: WO 98/42752; U.S. Patent Nos. 6,682,736 and 6,207, 156; Hurwitz et al, Proc. Natl. Acad. Sci. USA, 95(17): 10067-10071 (1998); Camacho et al, J. Clin. Oncol., 22(145): Abstract No. 2505 (2004) (antibody CP- 675206); Mokyr et al, Cancer Res., 58:5301-5304 (1998) (incorporated herein by reference).

[0087] In some embodiments, the CTLA-4 inhibitor is a CTLA-4 ligand as disclosed in WO1996040915.

[0088] In some embodiments, the CTLA-4 inhibitor is a nucleic acid inhibitor of

CTLA-4 expression. For example, anti-CTLA-4 RNAi molecules may take the form of the molecules described by Mello and Fire in PCT Publication Nos. WO 1999/032619 and WO 2001/029058; U.S. Publication Nos. 2003/0051263, 2003/0055020, 2003/0056235,

2004/265839, 2005/0100913, 2006/0024798, 2008/0050342, 2008/0081373, 2008/0248576, and 2008/055443; and/or U.S. Patent Nos. 6,506,559, 7,282,564, 7,538,095, and 7,560,438 (incorporated herein by reference). In some instances, the anti-CTLA-4 RNAi molecules take the form of double stranded RNAi molecules described by Tuschl in European Patent No. EP 1309726 (incorporated herein by reference). In some instances, the anti-CTLA-4 RNAi molecules take the form of double stranded RNAi molecules described by Tuschl in U.S. Patent Nos. 7,056,704 and 7,078, 196 (incorporated herein by reference). In some embodiments, the CTLA-4 inhibitor is an aptamer described in PCT Publication No.

WO2004081021 , such as Del 60 or M9- 14 del 55.

[0089] Additionally, the anti-CTLA-4 RNAi molecules of the present invention may take the form be RNA molecules described by Crooke in U.S. Patent Nos. 5,898,031, 6, 107,094, 7,432,249, and 7,432,250, and European Application No. EP 0928290

(incorporated herein by reference).

[0090] In some embodiments, a TEC inhibitor is administered in combination with a

CTLA-4 inhibitor described above and elsewhere for inducing tumor-specific immunological memory in a cancer. In some embodiments, the TEC inhibitor is a Btk inhibitor or an Itk inhibitor. In some embodiments, the TEC inhibitor is a Btk inhibitor. In some embodiments, the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila

Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene

Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene Corporation), AVL-291/CC- 291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI

Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA-056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486

(Hoffmann-La Roche), HM71224 (Hanmi Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-0853 (Genentech), or combinations thereof. In some embodiments, the BTK inhibitor is ibrutinib.

[0091] In some embodiments, a Btk inhibitor is administered in combination with a

CTLA-4 inhibitor for inducing tumor-specific immunological memory in a cancer. In some embodiments, the CTLA-4 inhibitor is selected from Bristol Meyers Squibb' s anti-CTLA-4 antibody ipilimumab (also known as Yervoy®, MDX-010, BMS-734016 and MDX-101); anti-CTLA4 Antibody, clone 9H10 from Millipore; Pfizer' s tremelimumab (CP-675,206, ticilimumab); anti-CTLA-4 antibody clone BNI3 from Abeam; Del 60; and M9-14 del 55. In some embodiments, a Btk inhibitor is administered in combination with a CTLA-4 inhibitor selected from Bristol Meyers Squibb' s anti-CTLA-4 antibody ipilimumab (also known as Yervoy®, MDX-010, BMS-734016 and MDX-101); anti-CTLA-4 Antibody, clone 9H10 from Millipore; Pfizer' s tremelimumab (CP-675,206, ticilimumab); anti-CTLA-4 antibody clone BNI3 from Abeam; Del 60; and M9-14 del 55 for inducing tumor-specific

immunological memory in a cancer.

[0092] In some embodiments, ibrutinib is administered in combination with a CTLA-

4 inhibitor for inducing tumor-specific immunological memory in a cancer. In some embodiments, the CTLA-4 inhibitor is selected from Bristol Meyers Squibb' s anti-CTLA-4 antibody ipilimumab (also known as Yervoy®, MDX-010, BMS-734016 and MDX-101); anti-CTLA-4 Antibody, clone 9H10 from Millipore; Pfizer' s tremelimumab (CP-675,206, ticilimumab); anti-CTLA-4 antibody clone BNI3 from Abeam; Del 60; and M9-14 del 55. In some embodiments, ibrutinib is administered in combination with a CTLA-4 inhibitor selected from Bristol Meyers Squibb' s anti-CTLA-4 antibody ipilimumab (also known as Yervoy®, MDX-010, BMS-734016 and MDX-101); anti-CTLA-4 Antibody, clone 9H10 from Millipore; Pfizer' s tremelimumab (CP-675,206, ticilimumab); anti-CTLA-4 antibody clone BNI3 from Abeam; Del 60; and M9-14 del 55 for inducing tumor-specific

immunological memory in a cancer.

LAG 3 Inhibitors

[0093] In some embodiments, the immunomodulating agent is an inhibitor of LAG3

(CD223). In some embodiments, the immunomodulating agent is an antibody against LAG3. In some embodiments, the immunomodulating agent is a monoclonal antibody against LAG3. In other or additional embodiments, the immunomodulating agent is a human or humanized antibody against LAG3. In additional embodiments, an antibody against LAG3 blocks the interaction of LAG3with major histocompatibility complex (MHC) class II molecules.

Exemplary antibodies against LAG3 include: anti-Lag-3 antibody clone eBioC9B7W

(C9B7W) from eBioscience; anti-Lag3 antibody LS-B2237 from LifeSpan Biosciences; IMP321 (ImmuFact) from Immutep; anti-Lag3 antibody BMS-986016; and the LAG- 3 chimeric antibody A9H12. In some embodiments, the anti-LAG3 antibody is an anti-LAG3 antibody disclosed in any of the following patent publications (herein incorporated by reference): WO2010019570; WO2008132601; or WO2004078928.

[0094] In some embodiments, a TEC inhibitor is administered in combination with a

LAG3 inhibitor described above and elsewhere for inducing tumor-specific immunological memory in a cancer. In some embodiments, the TEC inhibitor is a Btk inhibitor or an Itk inhibitor. In some embodiments, the TEC inhibitor is a Btk inhibitor. In some embodiments, the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila

Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene

Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene Corporation), AVL-291/CC- 291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI

Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA-056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486

(Hoffmann-La Roche), HM71224 (Hanmi Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-0853 (Genentech), or combinations thereof. In some embodiments, the BTK inhibitor is ibrutinib.

[0095] In some embodiments, a Btk inhibitor is administered in combination with a

LAG3 inhibitor for inducing tumor-specific immunological memory in a cancer. In some embodiments, the LAG3 inhibitor is selected from anti-Lag-3 antibody clone eBioC9B7W (C9B7W) from eBioscience; anti-Lag3 antibody LS-B2237 from LifeSpan Biosciences; IMP321 (ImmuFact) from Immutep; anti-Lag3 antibody BMS-986016; and the LAG- 3 chimeric antibody A9H12. In some embodiments, a Btk inhibitor is administered in combination with a LAG3 inhibitor selected from anti-Lag-3 antibody clone eBioC9B7W (C9B7W) from eBioscience; anti-Lag3 antibody LS-B2237 from LifeSpan Biosciences; IMP321 (ImmuFact) from Immutep; anti-Lag3 antibody BMS-986016; and the LAG- 3 chimeric antibody A9H12 for inducing tumor-specific immunological memory in a cancer. [0096] In some embodiments, ibrutinib is administered in combination with a LAG3 inhibitor for inducing tumor-specific immunological memory in a cancer. In some embodiments, the LAG3 inhibitor is selected from anti-Lag-3 antibody clone eBioC9B7W (C9B7W) from eBioscience; anti-Lag3 antibody LS-B2237 from LifeSpan Biosciences; IMP321 (ImmuFact) from Immutep; anti-Lag3 antibody BMS-986016; and the LAG- 3 chimeric antibody A9H12. In some embodiments, ibrutinib is administered in combination with a LAG3 inhibitor selected from anti-Lag-3 antibody clone eBioC9B7W (C9B7W) from eBioscience; anti-Lag3 antibody LS-B2237 from LifeSpan Biosciences; FMP321 (ImmuFact) from Immutep; anti-Lag3 antibody BMS-986016; and the LAG-3 chimeric antibody A9H12 for inducing tumor-specific immunological memory in a cancer.

TIM3 Inhibitors

[0097] In some embodiments, the immunomodulating agent is an antibody against

TFM3 (also known as HAVCR2). In some embodiments, the immunomodulating agent is a monoclonal antibody against TFM3. In other or additional embodiments, the

immunomodulating agent is a human or humanized antibody against TIM3. In additional embodiments, an antibody against TIM3 blocks the interaction of TIM3 with galectin-9 (Gal9). In some embodiments, the anti-TIM3 antibody is an anti-TFM3 antibody disclosed in any of the following patent publications (herein incorporated by reference): WO2013006490; WO201155607; WO2011159877; or WO200117057. In another embodiment, a TTM3 inhibitor is a TTM3 inhibitor disclosed in WO2009052623.

[0098] In some embodiments, a TEC inhibitor is administered in combination with a

TFM3 inhibitor described above and elsewhere for inducing tumor-specific immunological memory in a cancer. In some embodiments, the TEC inhibitor is a Btk inhibitor or an Itk inhibitor. In some embodiments, the TEC inhibitor is a Btk inhibitor. In some embodiments, the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila

Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene

Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene Corporation), AVL-291/CC- 291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI

Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA-056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486

(Hoffmann-La Roche), HM71224 (Hanmi Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-0853 (Genentech), or combinations thereof. In some embodiments, the Btk inhibitor is ibrutinib. In some embodiments, a Btk inhibitor is administered in combination with a TIM3 inhibitor for inducing tumor-specific immunological memory in a cancer. In some embodiments, ibrutinib is administered in combination with a TIM3 inhibitor for inducing tumor-specific

immunological memory in a cancer.

B7-H3 Inhibitors

[0099] In some embodiments, the immunomodulating agent is an antibody against

B7-H3. In one embodiment, the immunomodulating agent is MGA271. In some embodiments, a TEC inhibitor is administered in combination with a B7-H3 inhibitor (e.g. MGA271) for inducing tumor-specific immunological a cancer. In some embodiments, the TEC inhibitor is a Btk inhibitor or an Itk inhibitor. In some embodiments, the TEC inhibitor is a Btk inhibitor. In some embodiments, the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-101/CC- 101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila

Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene

Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA- 056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono

Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), HM71224 (Hanmi Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-0853 (Genentech), or combinations thereof. In some embodiments, the Btk inhibitor is ibrutinib. In some embodiments, a Btk inhibitor is administered in combination with a TIM3 inhibitor for inducing tumor-specific immunological memory in a cancer. In some embodiments, ibrutinib is administered in combination with a ΤΓΜ3 inhibitor for inducing tumor-specific immunological memory in a cancer. In some embodiments, a Btk inhibitor is administered in combination with a B7-H3 inhibitor (e.g. MGA271) for inducing tumor-specific

immunological memory in a cancer. In some embodiments, ibrutinib is administered in combination with a B7-H3 inhibitor (e.g. MGA271) for inducing tumor-specific

immunological memory in a cancer.

KIR Inhibitors [00100] In some embodiments, the immunomodulating agent is an antibody against

KIR. In one embodiment, the immunomodulating agent is Lirilumab (IPH2101). In some embodiments, an antibody against KIR blocks the interaction of KIR with HLA. In some embodiments, a TEC inhibitor is administered in combination with a KIR inhibitor (e.g. Lirilumab) for inducing tumor-specific immunological memory in a cancer. In some embodiments, the TEC inhibitor is a Btk inhibitor or an Itk inhibitor. In some embodiments, the TEC inhibitor is a Btk inhibitor. In some embodiments, the Btk inhibitor is ibrutinib, PCI- 45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL- 263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila

Therapeutics/Celgene Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene

Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS- 509744 (Bristol-Myers Squibb), CGI-1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA-056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), HM71224 (Hanmi

Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-0853 (Genentech), or combinations thereof. In some embodiments, the Btk inhibitor is ibrutinib. In some embodiments, a Btk inhibitor is administered in combination with a KIR inhibitor (e.g. Lirilumab) for inducing tumor-specific immunological memory in a cancer. In some embodiments, ibrutinib is administered in combination with a KIR inhibitor (e.g. Lirilumab) for inducing tumor-specific immunological memory in a cancer.

CD 137 Inhibitors

[00101] In some embodiments, the immunomodulating agent is an antibody against

CD137 (also known as 4-1BB or TNFRSF9). In one embodiment, the immunomodulating agent is urelumab (BMS-663513, Bristol-Myers Squibb), PF-05082566 (anti-4-lBB, PF- 2566, Pfizer), or XmAb-5592 (Xencor). In one embodiment, an anti-CD137 antibody is an antibody disclosed in U.S. Published Application No. US 2005/0095244; an antibody disclosed in issued U.S. Pat. No. 7,288,638 (such as 20H4.9-IgG4 [10C7 or BMS-663513] or 20H4.9-IgGl [BMS-663031]); an antibody disclosed in issued U.S. Pat. No. 6,887,673 [4E9 or BMS-554271]; an antibody disclosed in issued U.S. Pat. No. 7,214,493; an antibody disclosed in issued U.S. Pat. No. 6,303, 121; an antibody disclosed in issued U.S. Pat. No. 6,569,997; an antibody disclosed in issued U.S. Pat. No. 6,905,685; an antibody disclosed in issued U.S. Pat. No. 6,355,476; an antibody disclosed in issued U.S. Pat. No. 6,362,325 [1D8 or BMS-469492; 3H3 or BMS-469497; or 3E1]; an antibody disclosed in issued U.S. Pat. No. 6,974,863 (such as 53A2); or an antibody disclosed in issued U.S. Pat. No. 6,210,669 (such as 1D8, 3B8, or 3E1). In a further embodiment, the immunomodulating agent is one disclosed in WO 2014036412. In another embodiment, an antibody against CD137 blocks the interaction of CD137 with CD137L.

[00102] In some embodiments, a TEC inhibitor is administered in combination with a

CD137 inhibitor (e.g. urelumab, PF-05082566, XmAb-5592) for inducing tumor-specific immunological memory in a cancer. In some embodiments, the TEC inhibitor is a Btk inhibitor or an Itk inhibitor. In some embodiments, the TEC inhibitor is a Btk inhibitor. In some embodiments, the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene Corporation), AVL-291/CC- 291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI

Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA-056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486

(Hoffmann-La Roche), HM71224 (Hanmi Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-0853 (Genentech), or combinations thereof. In some embodiments, the Btk inhibitor is ibrutinib. In some

embodiments, a Btk inhibitor is administered in combination with a CD137 inhibitor (e.g. urelumab, PF-05082566, XmAb-5592) for inducing tumor-specific immunological memory in a cancer. In some embodiments, ibrutinib is administered in combination with a CD137 inhibitor (e.g. urelumab, PF-05082566, XmAb-5592) for inducing tumor-specific

immunological memory in a cancer.

PS Inhibitors

[00103] In some embodiments, the immunomodulating agent is an antibody against PS.

In one embodiment, the immunomodulating agent is Bavituximab. In some embodiments, a TEC inhibitor is administered in combination with a PS inhibitor (e.g. Bavituximab) for inducing tumor-specific immunological memory in a cancer. In some embodiments, the TEC inhibitor is a Btk inhibitor or an Itk inhibitor. In some embodiments, the TEC inhibitor is a Btk inhibitor. In some embodiments, the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene

Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA- 056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono

Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), HM71224 (Hanmi Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-0853 (Genentech), or combinations thereof. In some embodiments, the Btk inhibitor is ibrutinib. In some embodiments, a Btk inhibitor is administered in combination with a PS inhibitor (e.g. Bavituximab) for inducing tumor-specific immunological memory in a cancer. In some embodiments, ibrutinib is administered in combination with a PS inhibitor (e.g. Bavituximab) for inducing tumor-specific immunological memory in a cancer.

CD52 Inhibitors

[00104] In some embodiments, the immunomodulating agent is an antibody against

CD52. In one embodiment, the immunomodulating agent is alemtuzumab. In some embodiments, a TEC inhibitor is administered in combination with a CD52 inhibitor (e.g. alemtuzumab) for inducing tumor-specific immunological memory in a cancer. In some embodiments, the TEC inhibitor is a Btk inhibitor or an Itk inhibitor. In some embodiments, the TEC inhibitor is a Btk inhibitor. In some embodiments, the Btk inhibitor is ibrutinib, PCI- 45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL- 263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila

Therapeutics/Celgene Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene

Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS- 509744 (Bristol-Myers Squibb), CGI-1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA-056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), HM71224 (Hanmi

Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-0853 (Genentech), or combinations thereof. In some embodiments, the Btk inhibitor is ibrutinib. In some embodiments, a Btk inhibitor is administered in combination with a CD52 inhibitor (e.g. alemtuzumab) for inducing tumor-specific immunological memory in a cancer. In some embodiments, ibrutinib is administered in combination with a CD52 inhibitor (e.g. alemtuzumab) for inducing tumor-specific immunological memory in a cancer.

CD30 Inhibitors

[00105] In some embodiments, the immunomodulating agent is an antibody against

CD30. In one embodiment, the immunomodulating agent is brentuximab vedotin. In another embodiment, an antibody against CD30 blocks the interaction of CD30 with CD30L. In some embodiments, a TEC inhibitor is administered in combination with a CD30 inhibitor (e.g. brentuximab vedotin) for inducing tumor-specific immunological memory in a cancer. In some embodiments, the TEC inhibitor is a Btk inhibitor or an Itk inhibitor. In some embodiments, the TEC inhibitor is a Btk inhibitor. In some embodiments, the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene

Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC- 292 (Avila Therapeutics/Celgene Corporation), AVL-291/CC-291 (Avila

Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol- Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI-1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA-056, GDC-0834 (Genentech), HY- 11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), HM71224 (Hanmi Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-0853 (Genentech), or combinations thereof. In some embodiments, the Btk inhibitor is ibrutinib. In some embodiments, a Btk inhibitor is administered in combination with a CD30 inhibitor (e.g. brentuximab vedotin) for inducing tumor-specific immunological memory in a cancer. In some embodiments, ibrutinib is administered in combination with a CD30 inhibitor (e.g. brentuximab vedotin) for inducing tumor-specific immunological memory in a cancer.

CD33 Inhibitors

[00106] In some embodiments, the immunomodulating agent is an antibody against

CD33. In one embodiment, the immunomodulating agent is gemtuzumab ozogamicin. In some embodiments, a TEC inhibitor is administered in combination with a CD33 inhibitor (e.g. gemtuzumab ozogamicin) for inducing tumor-specific immunological memory in a cancer. In some embodiments, the TEC inhibitor is a Btk inhibitor or an Itk inhibitor. In some embodiments, the TEC inhibitor is a Btk inhibitor. In some embodiments, the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene

Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC- 292 (Avila Therapeutics/Celgene Corporation), AVL-291/CC-291 (Avila

Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol- Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI-1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA-056, GDC-0834 (Genentech), HY- 11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), HM71224 (Hanmi Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-0853 (Genentech), or combinations thereof. In some embodiments, the Btk inhibitor is ibrutinib. In some embodiments, a Btk inhibitor is administered in combination with a CD33 inhibitor (e.g. gemtuzumab ozogamicin) for inducing tumor-specific immunological memory in a cancer. In some embodiments, ibrutinib is administered in combination with a CD33 inhibitor (e.g. gemtuzumab ozogamicin) for inducing tumor-specific immunological memory in a cancer.

CD20 Inhibitors

[00107] In some embodiments, the immunomodulating agent is an antibody against

CD20. In one embodiment, the immunomodulating agent is ibritumomab tiuxetan. In another embodiment, the immunomodulating agent is ofatumumab. In another embodiment, the immunomodulating agent is rituximab. In another embodiment, the immunomodulating agent is tositumomab. In some embodiments, a TEC inhibitor is administered in combination with a CD20 inhibitor (e.g. ibritumomab tiuxetan, ofatumumab, rituximab, tositumomab) for inducing tumor-specific immunological memory in a cancer. In some embodiments, the TEC inhibitor is a BTK inhibitor or an ITK inhibitor. In some embodiments, the TEC inhibitor is a BTK inhibitor. In some embodiments, the BTK inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene

Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI-1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA- 056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), HM71224 (Hanmi Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-0853 (Genentech), or combinations thereof. In some embodiments, the BTK inhibitor is ibrutinib. In some embodiments, a BTK inhibitor is administered in combination with a CD20 inhibitor (e.g. ibritumomab tiuxetan, ofatumumab, rituximab, tositumomab) for inducing tumor- specific immunological memory in a cancer. In some embodiments, ibrutinib is administered in combination with a CD20 inhibitor (e.g. ibritumomab tiuxetan, ofatumumab, rituximab, tositumomab) for inducing tumor-specific immunological memory in a cancer.

CD27 Inhibitors

[00108] In some embodiments, the immunomodulating agent is an antibody against

CD27 (also known as T FRSF7). In one embodiment, the immunomodulating agent is CDX- 1127 (Celldex Therapeutics). In another embodiment, an antibody against CD27 blocks the interaction of CD27 with CD70. In some embodiments, a TEC inhibitor is administered in combination with a CD27 inhibitor (e.g. CDX-1127) for inducing tumor-specific

immunological memory in a cancer. In some embodiments, the TEC inhibitor is a BTK inhibitor or an ITK inhibitor. In some embodiments, the TEC inhibitor is a BTK inhibitor. In some embodiments, the BTK inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-101/CC- 101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila

Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene

Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA- 056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono

Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), HM71224 (Hanmi Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-0853 (Genentech), or combinations thereof. In some embodiments, the BTK inhibitor is ibrutinib. In some embodiments, a BTK inhibitor is administered in combination with a CD27 inhibitor (e.g. CDX-1127) for inducing tumor-specific immunological memory in a cancer. In some embodiments, ibrutinib is administered in combination with an OX40 inhibitor (e.g. CDX- 1127) for inducing tumor-specific immunological memory in a cancer.

OX40 Inhibitors [00109] In some embodiments, the immunomodulating agent is an antibody against

OX40 (also known as T FRSF4 or CD 134). In one embodiment, the immunomodulating agent is anti-OX40 mouse IgG. In another embodiment, an antibody against OX40 blocks the interaction of OX40 with OX40L. In some embodiments, a TEC inhibitor is administered in combination with an OX40 inhibitor (e.g. anti-OX40 mouse IgG) for inducing tumor-specific immunological memory in a cancer. In some embodiments, the TEC inhibitor is a Btk inhibitor or an Itk inhibitor. In some embodiments, the TEC inhibitor is a Btk inhibitor. In some embodiments, the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene Corporation), AVL-291/CC- 291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI

Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA-056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486

(Hoffmann-La Roche), HM71224 (Hanmi Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-0853 (Genentech), or combinations thereof . In some embodiments, the Btk inhibitor is ibrutinib. In some embodiments, a Btk inhibitor is administered in combination with an OX40 inhibitor (e.g. anti-OX40 mouse IgG) for inducing tumor-specific immunological memory in a cancer. In some embodiments, ibrutinib is administered in combination with an OX40 inhibitor (e.g. anti-OX40 mouse IgG) for inducing tumor-specific immunological memory in a cancer. GITR Inhibitors

[00110] In some embodiments, the immunomodulating agent is an antibody against glucocorticoid-induced tumor necrosis factor receptor (GITR). In one embodiment, the immunomodulating agent is TRX518 (GITR, Inc.). In another embodiment, an antibody against GITR blocks the interaction of GITR with GITRL. In some embodiments, a TEC inhibitor is administered in combination with a GITR inhibitor (e.g. TRX518) for inducing tumor-specific immunological memory in a cancer. In some embodiments, the TEC inhibitor is a Btk inhibitor or an Itk inhibitor. In some embodiments, the TEC inhibitor is a Btk inhibitor. In some embodiments, the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL- 101/CC-lOl (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila

Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA- 056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono

Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), HM71224 (Hanmi Pharmaceutical Company Limited) and LFM-A13. In some embodiments, the BTK inhibitor is ibrutinib. In some embodiments, a Btk inhibitor is administered in combination with a GITR inhibitor (e.g.

TRX518) for inducing tumor-specific immunological memory in a cancer. In some

embodiments, ibrutinib is administered in combination with an OX40 inhibitor (e.g. TRX518) for inducing tumor-specific immunological memory in a cancer.

ICOS Inhibitors

[00111] In some embodiments, the immunomodulating agent is an antibody against inducible T-cell COStimulator (ICOS, also known as CD278). In one embodiment, the immunomodulating agent is MEDI570 (Medlmmune, LLC) or AMG557 (Amgen). In another embodiment, an antibody against ICOS blocks the interaction of ICOS with ICOSL and/or B7-H2. In some embodiments, a TEC inhibitor is administered in combination with an ICOS inhibitor (e.g. MEDI570 or AMG557) for inducing tumor-specific immunological memory in a cancer. In some embodiments, the TEC inhibitor is a Btk inhibitor or an Itk inhibitor. In some embodiments, the TEC inhibitor is a Btk inhibitor. In some embodiments, the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC- 292 (Avila Therapeutics/Celgene Corporation), AVL-291/CC-291 (Avila

Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol- Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI-1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA-056, GDC-0834 (Genentech), HY- 11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), HM71224 (Hanmi Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-0853 (Genentech), or combinations thereof. In some embodiments, the Btk inhibitor is ibrutinib. In some embodiments, a Btk inhibitor is administered in combination with an ICOS inhibitor (e.g. MEDI570 or AMG557) for inducing tumor-specific immunological memory in a cancer. In some embodiments, ibrutinib is administered in combination with an OX40 inhibitor (e.g. MEDI570 or AMG557) for inducing tumor-specific immunological memory in a cancer.

Additional Immunomodulating agents

[00112] In some embodiments, the immunomodulating agent is an inhibitor against

BTLA (CD272), CD 160, 2B4, LAIRl, TIGHT, LIGHT, DR3, CD226, CD2, or SLAM. As described elsewhere herein, an immunomodulating agent can be one or more binding proteins, antibodies (or fragments or variants thereof) that bind to immune checkpoint molecules, nucleic acids that downregulate expression of the immune checkpoint molecules, or any other molecules that bind to immune checkpoint molecules (i.e. small organic molecules, peptidomimetics, aptamers, etc.). In some instances, an inhibitor of BTLA (CD272) is HVEM. In some instances, an inhibitor of CD 160 is HVEM. In some cases, an inhibitor of 2B4 is CD48. In some instances, an inhibitor of LAIRl is collagen. In some instances, an inhibitor of TIGHT is CD112, CD113, or CD155. In some instances, an inhibitor of CD28 is CD80 or CD86. In some instances, an inhibitor of LIGHT is HVEM. In some instances, an inhibitor of DR3 is TL1 A. In some instances, an inhibitor of CD226 is CD155 or CD112. In some cases, an inhibitor of CD2 is CD48 or CD58. In some cases, SLAM is self inhibitory and an inhibitor of SLAM is SLAM.

[00113] In some embodiments, a TEC inhibitor is administered in combination with an inhibitor against BTLA (CD272), CD160, 2B4, LAIRl, TIGHT, LIGHT, DR3, CD226, CD2, or SLAM for inducing tumor-specific immunological memory in a cancer. In some

embodiments, the TEC inhibitor is a Btk inhibitor or an Itk inhibitor. In some embodiments, the TEC inhibitor is a Btk inhibitor. In some embodiments, the Btk inhibitor is ibrutinib, PCI- 45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL- 263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila

Therapeutics/Celgene Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene

Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS- 509744 (Bristol-Myers Squibb), CGI-1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA-056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), HM71224 (Hanmi

Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-0853 (Genentech), or combinations thereof. In some embodiments, the Btk inhibitor is ibrutinib. In some embodiments, a Btk inhibitor is administered in combination with an inhibitor against BTLA (CD272), CD 160, 2B4, LAIRl, TIGHT, LIGHT, DR3, CD226, CD2, or SLAM for inducing tumor-specific immunological memory in a cancer. In some embodiments, ibrutinib is administered in combination with an inhibitor against BTLA (CD272), CD160, 2B4, LAIRl, TIGHT, LIGHT, DR3, CD226, CD2, or SLAM for inducing tumor-specific immunological memory in a cancer.

[00114] In some embodiments, a method of decreasing VEGF and/or decreasing VEGF secretion is provided. The method comprises the steps of administering a Btk inhibitor and an immunomodulating agent to an individual in need thereof. In some embodiments, the Btk inhibitor is ibrutinib and the immunomodulating agent is a CTLA-4 inhibitor.

[00115] In some embodiments, a method of reducing, decreasing, and/or inhibiting angiogenesis is provided. The method comprises the steps of administering a Btk inhibitor and an immunomodulating agent to an individual in need thereof. In some embodiments, the Btk inhibitor is ibrutinib and the immunomodulating agent is a CTLA-4 inhibitor. In some embodiments, methods of inhibiting VEGF are provided. The method comprises the steps of admistering a Btk inhibitor and an immunomodulating agent to an individual in need thereof.

VEGF

[00116] VEGF (vascular endothelial growth factor) can be secreted by tumor and stromal cells, including macrophages, endothelial cells and fibroblasts, has multiple functions in the tumor microenvironment. As the name suggests, VEGF stimulates vascular endothelial, growth, survival, and proliferation. VEGF is a member of 6 structurally related proteins (VEGF-A; VEGF-B; VEGF-C; VEGF-D; VEGF-E; and placental growth factors. VEGF stimulates angiogenesis, which is a process that involves the ability of VEGF receptors to stimulate signaling pathways that induce the proliferation and migration of endothelial cells, and the ability of these cells to degrade and to remodel the extracellular matrix. These processes cumulate in angiogenesis and formation of new blood vessels. VEGF ligands mediate their angiogenic effects by binding to specific VEGF receptors, leading to

subsequent signal transduction. VEGF secreted by tumor cells can enhance tumor invasion and survival.

Methods of Use [00117] Disclosed herein, in certain embodiments, is a method of inducing tumor- specific immunological memory in a cancer in an individual in need thereof which comprises administering a combination of a TEC inhibitor and an immunomodulating agent. In some embodiments, the TEC inhibitor is a BTK, ITK, TEC, RLK, or BMX inhibitor. In some embodiments, the TEC inhibitor is a Btk inhibitor or an Itk inhibitor. In some embodiments, the TEC inhibitor is a Btk inhibitor. In some embodiments, the Btk inhibitor is ibrutinib. In some embodiments, the combination provides a synergistic therapeutic effect compared to administration of ibrutinib or the immunomodulating agent alone. In some embodiments, the immunomodulating agent is an inhibitor of Programmed Death-Ligand 1 (PD-Ll, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-Ll, PD-1, CTLA-4, LAG3, or TEVI3. In some embodiments, the immunomodulating agent is an inhibitor of PD-Ll . In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TEVI3. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is a hematologic cancer.

[00118] Also disclosed herein, in some embodiments, is a method of inducing tumor- specific immunological memory in an ibrutinib-resistant cancer which comprises

administering to a subject in need thereof a therapeutically effective amount of a combination comprising: a) ibrutinib; and b) an immunomodulating agent. In some embodiments, the combination provides a synergistic therapeutic effect compared to administration of ibrutinib or the immunomodulating agent alone. In some embodiments, the immunomodulating agent is an inhibitor of Programmed Death-Ligand 1 (PD-Ll, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the

immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TIM3. In some embodiments, the ibrutinib-resistant cancer is a solid tumor. In some embodiments, the ibrutinib-resistant cancer is a hematologic cancer.

Solid Tumor

[00119] Disclosed herein, in certain embodiments, is a method of inducing tumor- specific immunological memory in a solid tumor in an individual in need thereof which comprises administering a combination of a TEC inhibitor and an immunomodulating agent. In some embodiments, the solid tumor is a sarcoma or carcinoma. In some embodiments, the solid tumor is a sarcoma. In some embodiments, the solid tumor is a carcinoma.

[00120] In some embodiments, the sarcoma is selected from alveolar

rhabdomyosarcoma; alveolar soft part sarcoma; ameloblastoma; angiosarcoma;

chondrosarcoma; chordoma; clear cell sarcoma of soft tissue; dedifferentiated liposarcoma; desmoid; desmoplastic small round cell tumor; embryonal rhabdomyosarcoma; epithelioid fibrosarcoma; epithelioid hemangioendothelioma; epithelioid sarcoma;

esthesioneuroblastoma; Ewing sarcoma; extrarenal rhabdoid tumor; extraskeletal myxoid chondrosarcoma; extraskeletal osteosarcoma; fibrosarcoma; giant cell tumor;

hemangiopericytoma; infantile fibrosarcoma; inflammatory myofibroblastic tumor; Kaposi sarcoma; leiomyosarcoma of bone; liposarcoma; liposarcoma of bone; malignant fibrous histiocytoma (MFH); malignant fibrous histiocytoma (MFH) of bone; malignant

mesenchymoma; malignant peripheral nerve sheath tumor; mesenchymal chondrosarcoma; myxofibrosarcoma; myxoid liposarcoma; myxoinflammatory fibroblastic sarcoma;

neoplasms with perivascular epitheioid cell differentiation; osteosarcoma; parosteal osteosarcoma; neoplasm with perivascular epitheioid cell differentiation; periosteal osteosarcoma; pleomorphic liposarcoma; pleomorphic rhabdomyosarcoma; P ET/extraskeletal Ewing tumor; rhabdomyosarcoma; round cell liposarcoma; small cell osteosarcoma; solitary fibrous tumor; synovial sarcoma; telangiectatic osteosarcoma.

[00121] In some embodiments, the carcinoma is selected from an adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, anaplastic carcinoma, large cell carcinoma, or small cell carcinoma. In some embodiments, the carcinoma is selected from anal cancer; appendix cancer; bile duct cancer (i.e., cholangiocarcinoma); bladder cancer; breast cancer; cervical cancer; colon cancer; cancer of Unknown Primary (CUP); esophageal cancer; eye cancer; fallopian tube cancer; gastroenterological cancer; kidney cancer; liver cancer; lung cancer; medulloblastoma; melanoma; oral cancer; ovarian cancer; pancreatic cancer; parathyroid disease; penile cancer; pituitary tumor; prostate cancer; rectal cancer; skin cancer; stomach cancer; testicular cancer; throat cancer; thyroid cancer; uterine cancer; vaginal cancer; or vulvar cancer. In some embodiments, the carcinoma is breast cancer. In some embodiments, the breast cancer is invasive ductal carcinoma, ductal carcinoma in situ, invasive lobular carcinoma, or lobular carcinoma in situ. In some embodiments, the carcinoma is pancreatic cancer. In some embodiments, the pancreatic cancer is

adenocarcinoma, or islet cell carcinoma. In some embodiments, the carcinoma is colorectal (colon) cancer. In some embodiments, the colorectal cancer is adenocarcinoma. In some embodiments, the solid tumor is a colon polyp. In some embodiments, the colon polyp is associated with familial adenomatous polyposis. In some embodiments, the carcinoma is bladder cancer. In some embodiments, the bladder cancer is transitional cell bladder cancer, squamous cell bladder cancer, or adenocarcinoma. In some embodiments, the bladder cancer is encompassed by the genitourinary tract cancers. In some embodiments, the genitourinary tract cancers also encompass kidney cancer, prostate cancer, and cancers associated with the reproductive organs. In some embodiments, the carcinoma is lung cancer. In some embodiments, the lung cancer is a non-small cell lung cancer. In some embodiments, the non- small cell lung cancer is adenocarcinoma, squamous-cell lung carcinoma, or large-cell lung carcinoma. In some embodiments, the lung cancer is a small cell lung cancer. In some embodiments, the carcinoma is prostate cancer. In some embodiments, the prostate cancer is adenocarcinoma or small cell carcinoma. In some embodiments, the carcinoma is ovarian cancer. In some embodiments, the ovarian cancer is epithelial ovarian cancer. In some embodiments, the carcinoma is bile duct cancer. In some embodiments, the bile duct cancer is proximal bile duct carcinoma or distal bile duct carcinoma.

[00122] In some embodiments, the solid tumor is selected from alveolar soft part sarcoma, bladder cancer, breast cancer, colorectal (colon) cancer, Ewing' s bone sarcoma, gastroenterological cancer, head and neck cancer, kidney cancer, leiomyosarcoma, lung cancer, melanoma, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, proximal or distal bile duct cancer, and neuroblastoma. In some embodiments, the solid tumor is prostate cancer. In some embodiments, the solid tumor is breast cancer. In some embodiments, the solid tumor is lung cancer. In some embodiments, the solid tumor is colorectal (colon) cancer. In some embodiments, the solid tumor is gastroenterological cancer. In some embodiments, the solid tumor is melanoma. In some embodiments, the solid tumor is lung cancer. In some embodiments, the solid tumor is kidney cancer. In some embodiments, the solid tumor is head and neck cancer. In some embodiments, the solid tumor is proximal or distal bile duct cancer. In some embodiments, the solid tumor is alveolar soft part sarcoma. In some embodiments, the solid tumor is Ewing's bone sarcoma. In some embodiments, the solid tumor is bladder cancer. In some embodiments, the solid tumor is ovarian cancer. In some embodiments, the solid tumor is leiomyosarcoma. In some embodiments, the solid tumor is osteosarcoma. In some embodiments, the solid tumor is neuroblastoma.

[00123] In some embodiments, the breast cancer is ductal carcinoma in situ

(intraductal carcinoma), lobular carcinoma in situ, invasive (or infiltrating) ductal carcinoma, invasive (or infiltrating) lobular carcinoma, inflammatory breast cancer, triple-negative breast cancer, paget disease of the nipple, phyllodes tumor, angiosarcoma or invasive breast carcinoma. In some embodiments, the invasive breast carcinoma is further categorized into subtypes. In some embodiments, the subtypes include adenoid cystic (or adenocystic) carcinoma, low-grade adenosquamous carcinoma, medullary carcinoma, mucinous (or colloid) carcinoma, papillary carcinoma, tubular carcinoma, metaplastic carcinoma, micropapillary carcinoma or mixed carcinoma.

[00124] In some embodiments, the breast cancer is classified according to stages or how far the tumor cells have spread within the breast tissues and to other portions of the body. In some embodiments, there are five stages of breast cancer, Stage 0-IV. In some

embodiments, Stage 0 breast cancer refers to non-invasive breast cancers or that there are no evidence of cancer cells or abnormal non-cancerous cells breaking out of the origin site. In some embodiments, Stage I breast cancer refers to invasive breast cancer in which the cancer cells have invaded into surrounding tissues. In some embodiments, Stage I is subclassified into Stage IA and IB, in which Stage IA describes tumor measures up to 2 cm with no spread of cancer cells. Stage IB describes absence of tumor in breast but have small lumps of cancer cells between 0.2mm to 2mm within the lymph nodes. In some embodiments, Stage II breast cancer is further subdivided into Stage IIA and IIB. In some embodiments, Stage IIA describes tumor between 2cm to 5 cm in breast only, or absence of tumor in breast but with cancer between 2mm to 2cm in axillary lymph nodes. In some embodiments, Stage IIB describes tumor larger than 5cm in breast only, or tumor between 2cm to 5 cm in breast with presence of small tumors from 0.2mm to 2mm in axillary lymph nodes. In some

embodiments, Stage III breast cancer is further subdivided into Stage IIIA, IIIB, and IIIC. In some embodiments, Stage IIIA describes absence of tumor or tumor greater than 5cm in breast with small tumors in 4-9 axillary lymph nodes or small tumors 0.2mm-2mm in size in axillary lymph nodes. In some embodiments, Stage IIIB describes tumor spreading into the chest wall or skin of the breast causing swelling or ulcer and with presence of tumor in up to 9 axillary lymph nodes. In some embodiments, inflammatory breast cancer is also considered as Stage IIIB. In some embodiments, Stage IIIC describes absence of tumor or tumor spreading into the chest wall or to the skin of the breast, with tumor present in 10 or more axillary lymph nodes. In some embodiments, Stage IV breast cancer refers to invasive breast cancer that has metastasized into the lymph nodes and other portions of the body.

[00125] In some embodiments, the colon cancer is a colorectal cancer. As used herein and throughout, "colon cancer" is used interchangeably with "colorectal cancer." In some embodiments, colorectal (colon) cancer refers to rectal cancer. In some embodiments, the colon cancer is adenocarcinoma, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors, primary colorectal lymphoma, leiomyosarcoma, melanoma, or squamous cell- carcinoma. In some embodiments, adenocarcinoma is a mucinous adenocarcinoma or a Signet ring cell adenocarcinoma.

[00126] In some embodiments, the colon cancer is classified according to stages or how far they have spread through the walls of the colon and rectum. In some embodiments, there are five stages of colon cancer, Stage 0-IV. In some embodiments, Stage 0 colon cancer refers to the very early stage of cancer. In some embodiments, Stage I colon cancer refers to when the cancer has spread beyond the innermost lining of the colon to the second and third layers and also involves the inside wall of the colon. In some embodiments, Stage II colon cancer refers to when the tumor has extended through the muscular wall but has not yet spread into the lymph nodes. In some embodiments, Stage III colon cancer refers to when the tumor has metastasized the colon into one or more lymph nodes. In some embodiments, Stage IV colon cancer refers to when the tumor has metastasized to other parts of the body. In some embodiments, there are two stages of rectal cancer, classified as Stage 0 and Stage I. In some embodiments, Stage 0 rectal cancer refers to when the tumor is located only on the inner lining of the rectum. In some embodiments, Stage I refers to when the tumor has advanced through the inner lining of the rectum but not yet reach past the muscular wall.

[00127] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a solid tumor in an individual in need thereof which comprises administering a combination of a TEC inhibitor and an immunomodulating agent. In some embodiments, the TEC inhibitor is a BTK, ITK, TEC, RLK, or BMX inhibitor. In some embodiments, the TEC inhibitor is a Btk inhibitor or an Itk inhibitor. In some embodiments, the TEC inhibitor is a Btk inhibitor. In some embodiments, the Btk inhibitor is ibrutinib. In some embodiments, the immunomodulating agent is an inhibitor of Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS

(phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some

embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the

immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the

immunomodulating agent is an inhibitor of LAG3. In some embodiments, the

immunomodulating agent is an inhibitor of TIM3. In some embodiments, the solid tumor is selected from alveolar soft part sarcoma, bladder cancer, breast cancer, colorectal (colon) cancer, Ewing's bone sarcoma, gastroenterological cancer, head and neck cancer, kidney cancer, leiomyosarcoma, lung cancer, melanoma, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, proximal or distal bile duct cancer, and neuroblastoma. In some embodiments, the solid tumor is prostate cancer. In some embodiments, the solid tumor is breast cancer. In some embodiments, the solid tumor is lung cancer. In some embodiments, the solid tumor is colorectal (colon) cancer. In some embodiments, the solid tumor is gastroenterological cancer. In some embodiments, the solid tumor is melanoma. In some embodiments, the solid tumor is lung cancer. In some embodiments, the solid tumor is kidney cancer. In some embodiments, the solid tumor is head and neck cancer. In some embodiments, the solid tumor is proximal or distal bile duct cancer. In some embodiments, the solid tumor is alveolar soft part sarcoma. In some embodiments, the solid tumor is Ewing's bone sarcoma. In some embodiments, the solid tumor is bladder cancer. In some embodiments, the solid tumor is ovarian cancer. In some embodiments, the solid tumor is leiomyosarcoma. In some embodiments, the solid tumor is osteosarcoma. In some embodiments, the solid tumor is neuroblastoma.

[00128] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a solid tumor in an individual in need thereof which comprises administering a combination of an Itk inhibitor and an immunomodulating agent. In some embodiments, the immunomodulating agent is an inhibitor of Programmed Death- Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS

(phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some

embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the

immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the

immunomodulating agent is an inhibitor of LAG3. In some embodiments, the

immunomodulating agent is an inhibitor of TIM3. In some embodiments, the solid tumor is selected from alveolar soft part sarcoma, bladder cancer, breast cancer, colorectal (colon) cancer, Ewing's bone sarcoma, gastroenterological cancer, genitourinary tract cancer, head and neck cancer, kidney cancer, leiomyosarcoma, lung cancer, melanoma, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, proximal or distal bile duct cancer, and neuroblastoma. In some embodiments, the solid tumor is prostate cancer. In some

embodiments, the solid tumor is breast cancer. In some embodiments, the solid tumor is lung cancer. In some embodiments, the solid tumor is colorectal (colon) cancer. In some

embodiments, the solid tumor is gastroenterological cancer. In some embodiments, the solid tumor is melanoma. In some embodiments, the solid tumor is lung cancer. In some embodiments, the solid tumor is kidney cancer. In some embodiments, the solid tumor is head and neck cancer. In some embodiments, the solid tumor is proximal or distal bile duct cancer. In some embodiments, the solid tumor is alveolar soft part sarcoma. In some embodiments, the solid tumor is Ewing's bone sarcoma. In some embodiments, the solid tumor is bladder cancer. In some embodiments, the solid tumor is ovarian cancer. In some embodiments, the solid tumor is leiomyosarcoma. In some embodiments, the solid tumor is osteosarcoma. In some embodiments, the solid tumor is neuroblastoma.

[00129] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a solid tumor in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an immunomodulating agent. In some embodiments, the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-101/CC- 101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila

Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene

Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA- 056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono

Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), HM71224 (Hanmi Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-0853 (Genentech), or combinations thereof. In some embodiments, the Btk inhibitor is ibrutinib. In some embodiments, the immunomodulating agent is an inhibitor of Programmed Death- Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, ΤΓΜ4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, NKG2A, PS

(phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some

embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the

immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the

immunomodulating agent is an inhibitor of LAG3. In some embodiments, the

immunomodulating agent is an inhibitor of TIM3. In some embodiments, the solid tumor is selected from alveolar soft part sarcoma, bladder cancer, breast cancer, colorectal (colon) cancer, Ewing's bone sarcoma, gastroenterological cancer, head and neck cancer, kidney cancer, leiomyosarcoma, lung cancer, melanoma, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, proximal or distal bile duct cancer, and neuroblastoma. In some embodiments, the solid tumor is prostate cancer. In some embodiments, the solid tumor is breast cancer. In some embodiments, the solid tumor is lung cancer. In some embodiments, the solid tumor is colorectal (colon) cancer. In some embodiments, the solid tumor is gastroenterological cancer. In some embodiments, the solid tumor is melanoma. In some embodiments, the solid tumor is lung cancer. In some embodiments, the solid tumor is kidney cancer. In some embodiments, the solid tumor is head and neck cancer. In some embodiments, the solid tumor is proximal or distal bile duct cancer. In some embodiments, the solid tumor is alveolar soft part sarcoma. In some embodiments, the solid tumor is Ewing's bone sarcoma. In some embodiments, the solid tumor is bladder cancer. In some embodiments, the solid tumor is ovarian cancer. In some embodiments, the solid tumor is leiomyosarcoma. In some embodiments, the solid tumor is osteosarcoma. In some embodiments, the solid tumor is neuroblastoma.

[00130] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a solid tumor in an individual in need thereof which comprises administering a combination of ibrutinib and an immunomodulating agent. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the

immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the

immunomodulating agent is an inhibitor of LAG3. In some embodiments, the

immunomodulating agent is an inhibitor of TIM3. In some embodiments, the solid tumor is selected from alveolar soft part sarcoma, bladder cancer, breast cancer, colorectal (colon) cancer, Ewing's bone sarcoma, gastroenterological cancer, head and neck cancer, kidney cancer, leiomyosarcoma, lung cancer, melanoma, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, proximal or distal bile duct cancer, and neuroblastoma. In some embodiments, the solid tumor is prostate cancer. In some embodiments, the solid tumor is breast cancer. In some embodiments, the solid tumor is lung cancer. In some embodiments, the solid tumor is colorectal (colon) cancer. In some embodiments, the solid tumor is gastroenterological cancer. In some embodiments, the solid tumor is melanoma. In some embodiments, the solid tumor is lung cancer. In some embodiments, the solid tumor is kidney cancer. In some embodiments, the solid tumor is head and neck cancer. In some embodiments, the solid tumor is proximal or distal bile duct cancer. In some embodiments, the solid tumor is alveolar soft part sarcoma. In some embodiments, the solid tumor is Ewing's bone sarcoma. In some embodiments, the solid tumor is bladder cancer. In some embodiments, the solid tumor is ovarian cancer. In some embodiments, the solid tumor is leiomyosarcoma. In some embodiments, the solid tumor is osteosarcoma. In some embodiments, the solid tumor is neuroblastoma.

[00131] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in an ibrutinib-resistant solid tumor in an individual in need thereof which comprises administering a combination of ibrutinib and an immunomodulating agent. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274),

Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TIM3. In some embodiments, the ibrutinib-resistant solid tumor is selected from alveolar soft part sarcoma, bladder cancer, breast cancer, colorectal (colon) cancer, Ewing's bone sarcoma, gastroenterological cancer, genitourinary tract cancer, head and neck cancer, kidney cancer, leiomyosarcoma, lung cancer, melanoma, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, proximal or distal bile duct cancer, and neuroblastoma. In some embodiments, the ibrutinib- resistant solid tumor is prostate cancer. In some embodiments, the ibrutinib-resistant solid tumor is breast cancer. In some embodiments, the ibrutinib-resistant solid tumor is lung cancer. In some embodiments, the ibrutinib-resistant solid tumor is colorectal (colon) cancer. In some embodiments, the ibrutinib-resistant solid tumor is gastroenterological cancer. In some embodiments, the ibrutinib-resistant solid tumor is melanoma. In some embodiments, the ibrutinib-resistant solid tumor is lung cancer. In some embodiments, the ibrutinib- resistant solid tumor is kidney cancer. In some embodiments, the ibrutinib-resistant solid tumor is head and neck cancer. In some embodiments, the ibrutinib-resistant solid tumor is proximal or distal bile duct cancer. In some embodiments, the ibrutinib-resistant solid tumor is alveolar soft part sarcoma. In some embodiments, the ibrutinib-resistant solid tumor is Ewing's bone sarcoma. In some embodiments, the ibrutinib-resistant solid tumor is bladder cancer. In some embodiments, the ibrutinib-resistant solid tumor is ovarian cancer. In some embodiments, the ibrutinib-resistant solid tumor is leiomyosarcoma. In some embodiments, the ibrutinib-resistant solid tumor is osteosarcoma. In some embodiments, the ibrutinib- resistant solid tumor is neuroblastoma.

[00132] In some embodiments, described herein is a method of inducing tumor- specific immunological memory a breast cancer in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an immunomodulating agent. In some embodiments, the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-101/CC- 101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila

Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene

Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA- 056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono

Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), HM71224 (Hanmi Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-0853 (Genentech), or combinations thereof. In some embodiments, the BTK inhibitor is ibrutinib. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some

embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the

immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the

immunomodulating agent is an inhibitor of LAG3. In some embodiments, the

immunomodulating agent is an inhibitor of TIM3.

[00133] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a breast cancer in an individual in need thereof which comprises administering a combination of ibrutinib and an immunomodulating agent. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, ΤΓΜ4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some

embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the

immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the

immunomodulating agent is an inhibitor of LAG3. In some embodiments, the

immunomodulating agent is an inhibitor of TIM3.

[00134] In some embodiments, described herein is a method of inducing tumor- specific immunological memory a colon cancer in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an immunomodulating agent. In some embodiments, the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-101/CC- 101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila

Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene

Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA- 056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono

Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), HM71224 (Hanmi Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-0853 (Genentech), or combinations thereof. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, ΤΓΜ3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or ΤΓΜ3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TIM3.

[00135] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a colon cancer in an individual in need thereof which comprises administering a combination of ibrutinib and an immunomodulating agent. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some

embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the

immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the

immunomodulating agent is an inhibitor of LAG3. In some embodiments, the

immunomodulating agent is an inhibitor of TIM3.

[00136] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a lung cancer in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an immunomodulating agent. In some embodiments, the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-101/CC- 101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila

Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene

Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA- 056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), HM71224 (Hanmi Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-0853 (Genentech), or combinations thereof. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TEVI3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TEVI3.

[00137] In some embodiments, described herein is a method of inducing tumor- specific immunological memory a lung cancer in an individual in need thereof which comprises administering a combination of ibrutinib and an immunomodulating agent. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some

embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the

immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the

immunomodulating agent is an inhibitor of LAG3. In some embodiments, the

immunomodulating agent is an inhibitor of TIM3.

[00138] In some embodiments, described herein is a method of inducing tumor- specific immunological memory a prostate cancer in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an immunomodulating agent. In some embodiments, the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-101/CC- 101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila

Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene

Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA- 056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono

Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), HM71224 (Hanmi Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-0853 (Genentech), or combinations thereof . In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, ΤΓΜ3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, NKG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or ΤΓΜ3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of ΤΓΜ3. [00139] In some embodiments, described herein is a method of inducing tumor- specific immunological memory a prostate cancer in an individual in need thereof which comprises administering a combination of ibrutinib and an immunomodulating agent. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some

embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the

immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the

immunomodulating agent is an inhibitor of LAG3. In some embodiments, the

immunomodulating agent is an inhibitor of TEVI3.

[00140] In some embodiments, described herein is a method of inducing tumor- specific immunological memory a pancreatic cancer in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an immunomodulating agent. In some embodiments, the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-101/CC- 101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila

Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene

Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA- 056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono

Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), HM71224 (Hanmi Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-0853 (Genentech), or combinations thereof . In some embodiments, the Btk inhibitor is ibrutinib. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some

embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the

immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the

immunomodulating agent is an inhibitor of LAG3. In some embodiments, the

immunomodulating agent is an inhibitor of TIM3.

[00141] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a pancreatic cancer in an individual in need thereof which comprises administering a combination of ibrutinib and an immunomodulating agent. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some

embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the

immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TIM3.

[00142] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in an ovarian cancer in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an immunomodulating agent. In some embodiments, the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-101/CC- 101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila

Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene

Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA- 056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono

Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), HM71224 (Hanmi Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-0853 (Genentech), or combinations thereof . In some embodiments, the Btk inhibitor is ibrutinib. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, ΤΓΜ4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, NKG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some

embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the

immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the

immunomodulating agent is an inhibitor of LAG3. In some embodiments, the

immunomodulating agent is an inhibitor of ΤΓΜ3. [00143] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in an ovarian cancer in an individual in need thereof which comprises administering a combination of ibrutinib and an immunomodulating agent. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some

embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the

immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the

immunomodulating agent is an inhibitor of LAG3. In some embodiments, the

immunomodulating agent is an inhibitor of TEVI3.

[00144] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a bladder cancer in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an immunomodulating agent. In some embodiments, the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-101/CC- 101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila

Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene

Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA- 056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono

Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), HM71224 (Hanmi Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-0853 (Genentech), or combinations thereof . In some embodiments, the BTK inhibitor is ibrutinib. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some

embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the

immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the

immunomodulating agent is an inhibitor of LAG3. In some embodiments, the

immunomodulating agent is an inhibitor of TIM3.

[00145] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a bladder cancer in an individual in need thereof which comprises administering a combination of ibrutinib and an immunomodulating agent. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some

embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the

immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TIM3.

[00146] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a proximal or distal bile duct cancer in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an immunomodulating agent. In some embodiments, the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA- 056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono

Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), HM71224 (Hanmi Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-0853 (Genentech), or combinations thereof . In some embodiments, the BTK inhibitor is ibrutinib. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, NKG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some

embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the

immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the

immunomodulating agent is an inhibitor of LAG3. In some embodiments, the

immunomodulating agent is an inhibitor of TEVI3. [00147] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a proximal or distal bile duct cancer in an individual in need thereof which comprises administering a combination of ibrutinib and an

immunomodulating agent. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7- Hl, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TEVI3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TEVI3.

[00148] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a melanoma cancer in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an immunomodulating agent. In some embodiments, the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-101/CC- 101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila

Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene

Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA- 056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono

Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), HM71224 (Hanmi Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-0853 (Genentech), or combinations thereof . In some embodiments, the BTK inhibitor is ibrutinib. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some

embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the

immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the

immunomodulating agent is an inhibitor of LAG3. In some embodiments, the

immunomodulating agent is an inhibitor of TIM3.

[00149] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a melanoma cancer in an individual in need thereof which comprises administering a combination of ibrutinib and an immunomodulating agent. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some

embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the

immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TIM3.

[00150] In some embodiments, a cancer is a treatment-naive cancer. In some instances, a treatment-naive cancer is a cancer that has not been treated by a therapy, such as for example by a TEC inhibitor, an immunomodulating agent, and/or by an additional therapeutic agent disclosed elsewhere herein. In some embodiments, a treatment-naive cancer is a solid tumor. In some embodiments, a treatment-naive solid tumor is a solid tumor such as bladder, breast, colon, pancreatic, lung, prostate, ovarian, proximal or distal bile duct cancer, or melanoma. In some embodiments, described herein is a method of inducing tumor-specific immunological memory in a treatment-naive solid tumor in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an immunomodulating agent. In some embodiments, the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL- 101/CC-lOl (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila

Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene

Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA- 056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono

Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), HM71224 (Hanmi Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-0853 (Genentech), or combinations thereof . In some embodiments, the BTK inhibitor is ibrutinib. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, NKG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the

immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the

immunomodulating agent is an inhibitor of LAG3. In some embodiments, the

immunomodulating agent is an inhibitor of TIM3.

Relapsed or Refractory Solid Tumor

[00151] In some embodiments, the solid tumor is a relapsed or refractory solid tumor.

In some embodiments, the relapsed or refractory solid tumor is a sarcoma or carcinoma. In some embodiments, the relapsed or refractory solid tumor is a sarcoma. In some

embodiments, the relapsed or refractory solid tumor is a carcinoma. In some embodiments, the sarcoma is selected from alveolar rhabdomyosarcoma; alveolar soft part sarcoma;

ameloblastoma; angiosarcoma; chondrosarcoma; chordoma; clear cell sarcoma of soft tissue; dedifferentiated liposarcoma; desmoid; desmoplastic small round cell tumor; embryonal rhabdomyosarcoma; epithelioid fibrosarcoma; epithelioid hemangioendothelioma; epithelioid sarcoma; esthesioneuroblastoma; Ewing sarcoma; extrarenal rhabdoid tumor; extraskeletal myxoid chondrosarcoma; extraskeletal osteosarcoma; fibrosarcoma; giant cell tumor;

hemangiopericytoma; infantile fibrosarcoma; inflammatory myofibroblastic tumor; Kaposi sarcoma; leiomyosarcoma of bone; liposarcoma; liposarcoma of bone; malignant fibrous histiocytoma (MFH); malignant fibrous histiocytoma (MFH) of bone; malignant

mesenchymoma; malignant peripheral nerve sheath tumor; mesenchymal chondrosarcoma; myxofibrosarcoma; myxoid liposarcoma; myxoinflammatory fibroblastic sarcoma;

neoplasms with perivascular epitheioid cell differentiation; osteosarcoma; parosteal osteosarcoma; neoplasm with perivascular epitheioid cell differentiation; periosteal osteosarcoma; pleomorphic liposarcoma; pleomorphic rhabdomyosarcoma;

P ET/extraskeletal Ewing tumor; rhabdomyosarcoma; round cell liposarcoma; small cell osteosarcoma; solitary fibrous tumor; synovial sarcoma; telangiectatic osteosarcoma. In some embodiments, the carcinoma is selected from an adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, anaplastic carcinoma, large cell carcinoma, or small cell carcinoma. In some embodiments, the carcinoma is selected from anal cancer; appendix cancer; bile duct cancer (i.e., cholangiocarcinoma); bladder cancer; breast cancer; cervical cancer; colon cancer; cancer of Unknown Primary (CUP); esophageal cancer; eye cancer; fallopian tube cancer; gastroenterological cancer; kidney cancer; liver cancer; lung cancer; medulloblastoma; melanoma; oral cancer; ovarian cancer; pancreatic cancer; parathyroid disease; penile cancer; pituitary tumor; prostate cancer; rectal cancer; skin cancer; stomach cancer; testicular cancer; throat cancer; thyroid cancer; uterine cancer; vaginal cancer; or vulvar cancer. In some embodiments, the carcinoma is breast cancer. In some embodiments, the breast cancer is invasive ductal carcinoma, ductal carcinoma in situ, invasive lobular carcinoma, or lobular carcinoma in situ. In some embodiments, the carcinoma is pancreatic cancer. In some embodiments, the pancreatic cancer is adenocarcinoma, or islet cell carcinoma. In some embodiments, the carcinoma is colorectal (colon) cancer. In some embodiments, the colorectal cancer is adenocarcinoma. In some embodiments, the solid tumor is a colon polyp. In some embodiments, the colon polyp is associated with familial adenomatous polyposis. In some embodiments, the carcinoma is bladder cancer. In some embodiments, the bladder cancer is transitional cell bladder cancer, squamous cell bladder cancer, or adenocarcinoma. In some embodiments, the carcinoma is lung cancer. In some embodiments, the lung cancer is a non-small cell lung cancer. In some embodiments, the non- small cell lung cancer is adenocarcinoma, squamous-cell lung carcinoma, or large-cell lung carcinoma. In some embodiments, the lung cancer is a small cell lung cancer. In some embodiments, the carcinoma is prostate cancer. In some embodiments, the prostate cancer is adenocarcinoma or small cell carcinoma. In some embodiments, the carcinoma is ovarian cancer. In some embodiments, the ovarian cancer is epithelial ovarian cancer. In some embodiments, the carcinoma is bile duct cancer. In some embodiments, the bile duct cancer is proximal bile duct carcinoma or distal bile duct carcinoma.

[00152] In some embodiments, the relapsed or refractory solid tumor is selected from alveolar soft part sarcoma, bladder cancer, breast cancer, colorectal (colon) cancer, Ewing's bone sarcoma, gastroenterological cancer, head and neck cancer, kidney cancer,

leiomyosarcoma, lung cancer, melanoma, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, proximal or distal bile duct cancer, and neuroblastoma. In some

embodiments, the relapsed or refractory solid tumor is prostate cancer. In some embodiments, the relapsed or refractory solid tumor is breast cancer. In some embodiments, the relapsed or refractory solid tumor is lung cancer. In some embodiments, the relapsed or refractory solid tumor is colorectal (colon) cancer. In some embodiments, the relapsed or refractory solid tumor is gastroenterological cancer. In some embodiments, the relapsed or refractory solid tumor is melanoma. In some embodiments, the relapsed or refractory solid tumor is lung cancer. In some embodiments, the relapsed or refractory solid tumor is kidney cancer. In some embodiments, the relapsed or refractory solid tumor is head and neck cancer. In some embodiments, the relapsed or refractory solid tumor is proximal or distal bile duct cancer. In some embodiments, the relapsed or refractory solid tumor is alveolar soft part sarcoma. In some embodiments, the relapsed or refractory solid tumor is Ewing's bone sarcoma. In some embodiments, the relapsed or refractory solid tumor is bladder cancer. In some embodiments, the relapsed or refractory solid tumor is ovarian cancer. In some embodiments, the relapsed or refractory solid tumor is leiomyosarcoma. In some embodiments, the relapsed or refractory solid tumor is osteosarcoma. In some embodiments, the relapsed or refractory solid tumor is neuroblastoma.

[00153] In some embodiments, the relapsed or refractory solid tumor is a relapsed or refractory breast cancer. In some embodiments, the relapsed or refractory breast cancer is ductal carcinoma in situ (intraductal carcinoma), lobular carcinoma in situ, invasive (or infiltrating) ductal carcinoma, invasive (or infiltrating) lobular carcinoma, inflammatory breast cancer, triple-negative breast cancer, paget disease of the nipple, phyllodes tumor, angiosarcoma or invasive breast carcinoma. In some embodiments, the invasive breast carcinoma is further categorized into subtypes. In some embodiments, the subtypes include adenoid cystic (or adenocystic) carcinoma, low-grade adenosquamous carcinoma, medullary carcinoma, mucinous (or colloid) carcinoma, papillary carcinoma, tubular carcinoma, metaplastic carcinoma, micropapillary carcinoma or mixed carcinoma.

[00154] In some embodiments, the relapsed or refractory solid tumor is a relapsed or refractory colon cancer. In some embodiments, the relapsed or refractory colon cancer is adenocarcinoma, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors, primary colorectal lymphoma, leiomyosarcoma, melanoma, squamous cell-carcinoma, mucinous adenocarcinoma, or Signet ring cell adenocarcinoma.

[00155] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a relapsed or refractory solid tumor in an individual in need thereof which comprises administering a combination of a TEC inhibitor and an immunomodulating agent. In some embodiments, the individual has relapsed or has developed a refractory solid tumor to an existing therapy. In some embodiments, the TEC inhibitor is a BTK, ITK, TEC, RLK, or BMX inhibitor. In some embodiments, the TEC inhibitor is a Btk inhibitor or an Itk inhibitor. In some embodiments, the TEC inhibitor is a Btk inhibitor. In some embodiments, the Btk inhibitor is ibrutinib. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD 112, CD 113, CD 137, CD137L, CD 155, CD 160, CD226, CD276, CRT AM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX- 40, OX40L, SLAM, TD02, TIGHT, TLIA, VISTA, VTCNl, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some embodiments, the

immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the

immunomodulating agent is an inhibitor of PD-1. In some embodiments, the

immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the

immunomodulating agent is an inhibitor of LAG3. In some embodiments, the

immunomodulating agent is an inhibitor of TIM3. In some embodiments, the relapsed or refractory solid tumor is selected from alveolar soft part sarcoma, bladder cancer, breast cancer, colorectal (colon) cancer, Ewing's bone sarcoma, gastroenterological cancer, head and neck cancer, kidney cancer, leiomyosarcoma, lung cancer, melanoma, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, proximal or distal bile duct cancer, and neuroblastoma. In some embodiments, the relapsed or refractory solid tumor is prostate cancer. In some embodiments, the relapsed or refractory solid tumor is breast cancer. In some embodiments, the relapsed or refractory solid tumor is lung cancer. In some embodiments, the relapsed or refractory solid tumor is colorectal (colon) cancer. In some embodiments, the relapsed or refractory solid tumor is gastroenterological cancer. In some embodiments, the relapsed or refractory solid tumor is melanoma. In some embodiments, the relapsed or refractory solid tumor is lung cancer. In some embodiments, the relapsed or refractory solid tumor is kidney cancer. In some embodiments, the relapsed or refractory solid tumor is head and neck cancer. In some embodiments, the relapsed or refractory solid tumor is proximal or distal bile duct cancer. In some embodiments, the relapsed or refractory solid tumor is alveolar soft part sarcoma. In some embodiments, the relapsed or refractory solid tumor is Ewing's bone sarcoma. In some embodiments, the relapsed or refractory solid tumor is bladder cancer. In some embodiments, the relapsed or refractory solid tumor is ovarian cancer. In some embodiments, the relapsed or refractory solid tumor is leiomyosarcoma. In some embodiments, the relapsed or refractory solid tumor is osteosarcoma. In some embodiments, the relapsed or refractory solid tumor is neuroblastoma.

[00156] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a relapsed or refractory solid tumor in an individual in need thereof which comprises administering a combination of an Itk inhibitor and an immunomodulating agent. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7- Hl, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TIM3. In some embodiments, the relapsed or refractory solid tumor is selected from alveolar soft part sarcoma, bladder cancer, breast cancer, colorectal (colon) cancer, Ewing's bone sarcoma, gastroenterological cancer, head and neck cancer, kidney cancer, leiomyosarcoma, lung cancer, melanoma, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, proximal or distal bile duct cancer, and neuroblastoma. In some embodiments, the relapsed or refractory solid tumor is prostate cancer. In some embodiments, the relapsed or refractory solid tumor is breast cancer. In some embodiments, the relapsed or refractory solid tumor is lung cancer. In some embodiments, the relapsed or refractory solid tumor is colorectal (colon) cancer. In some embodiments, the relapsed or refractory solid tumor is gastroenterological cancer. In some embodiments, the relapsed or refractory solid tumor is melanoma. In some embodiments, the relapsed or refractory solid tumor is lung cancer. In some embodiments, the relapsed or refractory solid tumor is kidney cancer. In some embodiments, the relapsed or refractory solid tumor is head and neck cancer. In some embodiments, the relapsed or refractory solid tumor is proximal or distal bile duct cancer. In some embodiments, the relapsed or refractory solid tumor is alveolar soft part sarcoma. In some embodiments, the relapsed or refractory solid tumor is Ewing's bone sarcoma. In some embodiments, the relapsed or refractory solid tumor is bladder cancer. In some embodiments, the relapsed or refractory solid tumor is ovarian cancer. In some embodiments, the relapsed or refractory solid tumor is leiomyosarcoma. In some embodiments, the relapsed or refractory solid tumor is

osteosarcoma. In some embodiments, the relapsed or refractory solid tumor is neuroblastoma.

[00157] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a relapsed or refractory solid tumor in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an immunomodulating agent. In some embodiments, the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA- 056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono

Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), HM71224 (Hanmi Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-0853 (Genentech), or combinations thereof . In some embodiments, the BTK inhibitor is ibrutinib. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, NKG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some

embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the

immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the

immunomodulating agent is an inhibitor of LAG3. In some embodiments, the

immunomodulating agent is an inhibitor of TIM3. In some embodiments, the relapsed or refractory solid tumor is selected from alveolar soft part sarcoma, bladder cancer, breast cancer, colorectal (colon) cancer, Ewing's bone sarcoma, gastroenterological cancer, head and neck cancer, kidney cancer, leiomyosarcoma, lung cancer, melanoma, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, proximal or distal bile duct cancer, and neuroblastoma. In some embodiments, the relapsed or refractory solid tumor is prostate cancer. In some embodiments, the relapsed or refractory solid tumor is breast cancer. In some embodiments, the relapsed or refractory solid tumor is lung cancer. In some embodiments, the relapsed or refractory solid tumor is colorectal (colon) cancer. In some embodiments, the relapsed or refractory solid tumor is gastroenterological cancer. In some embodiments, the relapsed or refractory solid tumor is melanoma. In some embodiments, the relapsed or refractory solid tumor is lung cancer. In some embodiments, the relapsed or refractory solid tumor is kidney cancer. In some embodiments, the relapsed or refractory solid tumor is head and neck cancer. In some embodiments, the relapsed or refractory solid tumor is proximal or distal bile duct cancer. In some embodiments, the relapsed or refractory solid tumor is alveolar soft part sarcoma. In some embodiments, the relapsed or refractory solid tumor is Ewing's bone sarcoma. In some embodiments, the relapsed or refractory solid tumor is bladder cancer. In some embodiments, the relapsed or refractory solid tumor is ovarian cancer. In some embodiments, the relapsed or refractory solid tumor is leiomyosarcoma. In some embodiments, the relapsed or refractory solid tumor is osteosarcoma. In some embodiments, the relapsed or refractory solid tumor is neuroblastoma.

[00158] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a relapsed or refractory solid tumor in an individual in need thereof which comprises administering a combination of ibrutinib and an

immunomodulating agent. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7- Hl, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TEVI3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TIM3. In some embodiments, the relapsed or refractory solid tumor is selected from alveolar soft part sarcoma, bladder cancer, breast cancer, colorectal (colon) cancer, Ewing's bone sarcoma, gastroenterological cancer, head and neck cancer, kidney cancer, leiomyosarcoma, lung cancer, melanoma, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, proximal or distal bile duct cancer, and neuroblastoma. In some embodiments, the relapsed or refractory solid tumor is prostate cancer. In some embodiments, the relapsed or refractory solid tumor is breast cancer. In some embodiments, the relapsed or refractory solid tumor is lung cancer. In some embodiments, the relapsed or refractory solid tumor is colorectal (colon) cancer. In some embodiments, the relapsed or refractory solid tumor is gastroenterological cancer. In some embodiments, the relapsed or refractory solid tumor is melanoma. In some embodiments, the relapsed or refractory solid tumor is lung cancer. In some embodiments, the relapsed or refractory solid tumor is kidney cancer. In some embodiments, the relapsed or refractory solid tumor is head and neck cancer. In some embodiments, the relapsed or refractory solid tumor is proximal or distal bile duct cancer. In some embodiments, the relapsed or refractory solid tumor is alveolar soft part sarcoma. In some embodiments, the relapsed or refractory solid tumor is Ewing's bone sarcoma. In some embodiments, the relapsed or refractory solid tumor is bladder cancer. In some embodiments, the relapsed or refractory solid tumor is ovarian cancer. In some embodiments, the relapsed or refractory solid tumor is

leiomyosarcoma. In some embodiments, the relapsed or refractory solid tumor is

osteosarcoma. In some embodiments, the relapsed or refractory solid tumor is neuroblastoma.

[00159] In some embodiments, a relapsed or refractory solid tumor is a relapsed or refractory ibrutinib-resistant solid tumor. In some embodiments, described herein is a method of inducing tumor-specific immunological memory in a relapsed or refractory ibrutinib- resistant solid tumor in an individual in need thereof which comprises administering a combination of ibrutinib and an immunomodulating agent. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD 112, CD 113, CD 137, CD137L, CD 155, CD 160, CD226, CD276, CRT AM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX- 40, OX40L, SLAM, TD02, TIGHT, TLIA, VISTA, VTCNl, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some embodiments, the

immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the

immunomodulating agent is an inhibitor of PD-1. In some embodiments, the

immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the

immunomodulating agent is an inhibitor of LAG3. In some embodiments, the

immunomodulating agent is an inhibitor of TIM3. In some embodiments, the relapsed or refractory ibrutinib-resistant solid tumor is selected from alveolar soft part sarcoma, bladder cancer, breast cancer, colorectal (colon) cancer, Ewing's bone sarcoma, gastroenterological cancer, head and neck cancer, kidney cancer, leiomyosarcoma, lung cancer, melanoma, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, proximal or distal bile duct cancer, and neuroblastoma. In some embodiments, the relapsed or refractory ibrutinib- resistant solid tumor is prostate cancer. In some embodiments, the relapsed or refractory ibrutinib-resistant solid tumor is breast cancer. In some embodiments, the relapsed or refractory ibrutinib-resistant solid tumor is lung cancer. In some embodiments, the relapsed or refractory ibrutinib-resistant solid tumor is colorectal (colon) cancer. In some

embodiments, the relapsed or refractory ibrutinib-resistant solid tumor is gastroenterological cancer. In some embodiments, the relapsed or refractory ibrutinib-resistant solid tumor is melanoma. In some embodiments, the relapsed or refractory ibrutinib-resistant solid tumor is lung cancer. In some embodiments, the relapsed or refractory ibrutinib-resistant solid tumor is kidney cancer. In some embodiments, the relapsed or refractory ibrutinib-resistant solid tumor is head and neck cancer. In some embodiments, the relapsed or refractory ibrutinib- resistant solid tumor is proximal or distal bile duct cancer. In some embodiments, the relapsed or refractory ibrutinib-resistant solid tumor is alveolar soft part sarcoma. In some embodiments, the relapsed or refractory ibrutinib-resistant solid tumor is Ewing's bone sarcoma. In some embodiments, the relapsed or refractory ibrutinib-resistant solid tumor is bladder cancer. In some embodiments, the relapsed or refractory ibrutinib-resistant solid tumor is ovarian cancer. In some embodiments, the relapsed or refractory ibrutinib-resistant solid tumor is leiomyosarcoma. In some embodiments, the relapsed or refractory ibrutinib- resistant solid tumor is osteosarcoma. In some embodiments, the relapsed or refractory ibrutinib-resistant solid tumor is neuroblastoma.

[00160] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a relapsed or refractory breast cancer in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an immunomodulating agent. In some embodiments, the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA- 056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono

Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), HM71224 (Hanmi Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-0853 (Genentech), or combinations thereof . In some embodiments, the Btk inhibitor is ibrutinib. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, NKG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some

embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the

immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the

immunomodulating agent is an inhibitor of LAG3. In some embodiments, the

immunomodulating agent is an inhibitor of TIM3. [00161] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a relapsed or refractory breast cancer in an individual in need thereof which comprises administering a combination of ibrutinib and an

immunomodulating agent. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7- Hl, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TEVI3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TEVI3.

[00162] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a relapsed or refractory colon cancer in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an immunomodulating agent. In some embodiments, the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA- 056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono

Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), HM71224 (Hanmi Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-0853 (Genentech), or combinations thereof . In some embodiments, the Btk inhibitor is ibrutinib. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some

embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the

immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the

immunomodulating agent is an inhibitor of LAG3. In some embodiments, the

immunomodulating agent is an inhibitor of TIM3.

[00163] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a relapsed or refractory colon cancer in an individual in need thereof which comprises administering a combination of ibrutinib and an

immunomodulating agent. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7- Hl, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TEVI3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TIM3.

[00164] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a relapsed or refractory lung cancer in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an immunomodulating agent. In some embodiments, the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA- 056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono

Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), HM71224 (Hanmi Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-0853 (Genentech), or combinations thereof . In some embodiments, the Btk inhibitor is ibrutinib. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, NKG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some

embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the

immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the

immunomodulating agent is an inhibitor of LAG3. In some embodiments, the

immunomodulating agent is an inhibitor of TEVI3. [00165] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a relapsed or refractory lung cancer in an individual in need thereof which comprises administering a combination of ibrutinib and an

immunomodulating agent. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7- Hl, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TEVI3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TEVI3.

[00166] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a relapsed or refractory prostate cancer in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an immunomodulating agent. In some embodiments, the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA- 056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono

Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), HM71224 (Hanmi Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-0853 (Genentech), or combinations thereof . In some embodiments, the Btk inhibitor is ibrutinib. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some

embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the

immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the

immunomodulating agent is an inhibitor of LAG3. In some embodiments, the

immunomodulating agent is an inhibitor of TIM3.

[00167] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a relapsed or refractory prostate cancer in an individual in need thereof which comprises administering a combination of ibrutinib and an

immunomodulating agent. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7- Hl, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TEVI3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TIM3.

[00168] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a relapsed or refractory pancreatic cancer in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an immunomodulating agent. In some embodiments, the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA- 056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono

Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), HM71224 (Hanmi Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-0853 (Genentech), or combinations thereof . In some embodiments, the Btk inhibitor is ibrutinib. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, NKG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some

embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the

immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the

immunomodulating agent is an inhibitor of LAG3. In some embodiments, the

immunomodulating agent is an inhibitor of TEVI3. [00169] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a relapsed or refractory pancreatic cancer in an individual in need thereof which comprises administering a combination of ibrutinib and an

immunomodulating agent. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7- Hl, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TEVI3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TEVI3.

[00170] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a relapsed or refractory ovarian cancer in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an immunomodulating agent. In some embodiments, the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA- 056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono

Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), HM71224 (Hanmi Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-0853 (Genentech), or combinations thereof . In some embodiments, the Btk inhibitor is ibrutinib. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some

embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the

immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the

immunomodulating agent is an inhibitor of LAG3. In some embodiments, the

immunomodulating agent is an inhibitor of TIM3.

[00171] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a relapsed or refractory ovarian cancer in an individual in need thereof which comprises administering a combination of ibrutinib and an

immunomodulating agent. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7- Hl, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TEVI3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TIM3.

[00172] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a relapsed or refractory bladder cancer in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an immunomodulating agent. In some embodiments, the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA- 056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono

Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), HM71224 (Hanmi Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-0853 (Genentech), or combinations thereof . In some embodiments, the Btk inhibitor is ibrutinib. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, NKG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some

embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the

immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the

immunomodulating agent is an inhibitor of LAG3. In some embodiments, the

immunomodulating agent is an inhibitor of TEVI3. [00173] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a relapsed or refractory bladder cancer in an individual in need thereof which comprises administering a combination of ibrutinib and an

immunomodulating agent. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7- Hl, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TEVI3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TEVI3.

[00174] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a relapsed or refractory proximal or distal bile duct cancer in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an immunomodulating agent. In some embodiments, the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene

Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC- 292 (Avila Therapeutics/Celgene Corporation), AVL-291/CC-291 (Avila

Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol- Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI-1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA-056, GDC-0834 (Genentech), HY- 11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), HM71224 (Hanmi Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-0853 (Genentech), or combinations thereof . In some embodiments, the Btk inhibitor is ibrutinib. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD 112, CD 113, CD 137, CD137L, CD 155, CD 160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX- 40, OX40L, SLAM, TD02, TIGHT, TLIA, VISTA, VTCNl, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some embodiments, the

immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the

immunomodulating agent is an inhibitor of PD-1. In some embodiments, the

immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the

immunomodulating agent is an inhibitor of LAG3. In some embodiments, the

immunomodulating agent is an inhibitor of TIM3.

[00175] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a relapsed or refractory proximal or distal bile duct cancer in an individual in need thereof which comprises administering a combination of ibrutinib and an immunomodulating agent. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7- Hl, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, NKG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TLIA, VISTA, VTCNl, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TEVI3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TIM3.

[00176] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a relapsed or refractory melanoma in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an immunomodulating agent. In some embodiments, the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA- 056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono

Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), HM71224 (Hanmi Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-0853 (Genentech), or combinations thereof . In some embodiments, the Btk inhibitor is ibrutinib. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, NKG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some

embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the

immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the

immunomodulating agent is an inhibitor of LAG3. In some embodiments, the

immunomodulating agent is an inhibitor of TEVI3. [00177] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a relapsed or refractory melanoma in an individual in need thereof which comprises administering a combination of ibrutinib and an

immunomodulating agent. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7- Hl, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TEVI3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TEVI3.

Metastasized Solid Tumor

[00178] In some embodiments, the solid tumor is a metastasized solid tumor. In some embodiments, the metastasized solid tumor is a sarcoma or carcinoma. In some embodiments, the metastasized solid tumor is a sarcoma. In some embodiments, the metastasized solid tumor is a carcinoma. In some embodiments, the sarcoma is selected from alveolar rhabdomyosarcoma; alveolar soft part sarcoma; ameloblastoma; angiosarcoma;

chondrosarcoma; chordoma; clear cell sarcoma of soft tissue; dedifferentiated liposarcoma; desmoid; desmoplastic small round cell tumor; embryonal rhabdomyosarcoma; epithelioid fibrosarcoma; epithelioid hemangioendothelioma; epithelioid sarcoma;

esthesioneuroblastoma; Ewing sarcoma; extrarenal rhabdoid tumor; extraskeletal myxoid chondrosarcoma; extraskeletal osteosarcoma; fibrosarcoma; giant cell tumor;

hemangiopericytoma; infantile fibrosarcoma; inflammatory myofibroblasts tumor; Kaposi sarcoma; leiomyosarcoma of bone; liposarcoma; liposarcoma of bone; malignant fibrous histiocytoma (MFH); malignant fibrous histiocytoma (MFH) of bone; malignant

mesenchymoma; malignant peripheral nerve sheath tumor; mesenchymal chondrosarcoma; myxofibrosarcoma; myxoid liposarcoma; myxoinflammatory fibroblastic sarcoma;

neoplasms with perivascular epitheioid cell differentiation; osteosarcoma; parosteal osteosarcoma; neoplasm with perivascular epitheioid cell differentiation; periosteal osteosarcoma; pleomorphic liposarcoma; pleomorphic rhabdomyosarcoma;

P ET/extraskeletal Ewing tumor; rhabdomyosarcoma; round cell liposarcoma; small cell osteosarcoma; solitary fibrous tumor; synovial sarcoma; telangiectatic osteosarcoma. In some embodiments, the carcinoma is selected from an adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, anaplastic carcinoma, large cell carcinoma, or small cell carcinoma. In some embodiments, the carcinoma is selected from anal cancer; appendix cancer; bile duct cancer (i.e., cholangiocarcinoma); bladder cancer; breast cancer; cervical cancer; colon cancer; cancer of Unknown Primary (CUP); esophageal cancer; eye cancer; fallopian tube cancer; gastroenterological cancer; kidney cancer; liver cancer; lung cancer; medulloblastoma; melanoma; oral cancer; ovarian cancer; pancreatic cancer; parathyroid disease; penile cancer; pituitary tumor; prostate cancer; rectal cancer; skin cancer; stomach cancer; testicular cancer; throat cancer; thyroid cancer; uterine cancer; vaginal cancer; or vulvar cancer. In some embodiments, the carcinoma is breast cancer. In some embodiments, the breast cancer is invasive ductal carcinoma, ductal carcinoma in situ, invasive lobular carcinoma, or lobular carcinoma in situ. In some embodiments, the carcinoma is pancreatic cancer. In some embodiments, the pancreatic cancer is adenocarcinoma, or islet cell carcinoma. In some embodiments, the carcinoma is colorectal (colon) cancer. In some embodiments, the colorectal cancer is adenocarcinoma. In some embodiments, the solid tumor is a colon polyp. In some embodiments, the colon polyp is associated with familial adenomatous polyposis. In some embodiments, the carcinoma is bladder cancer. In some embodiments, the bladder cancer is transitional cell bladder cancer, squamous cell bladder cancer, or adenocarcinoma. In some embodiments, the carcinoma is lung cancer. In some embodiments, the lung cancer is a non-small cell lung cancer. In some embodiments, the non- small cell lung cancer is adenocarcinoma, squamous-cell lung carcinoma, or large-cell lung carcinoma. In some embodiments, the lung cancer is a small cell lung cancer. In some embodiments, the carcinoma is prostate cancer. In some embodiments, the prostate cancer is adenocarcinoma or small cell carcinoma. In some embodiments, the carcinoma is ovarian cancer. In some embodiments, the ovarian cancer is epithelial ovarian cancer. In some embodiments, the carcinoma is bile duct cancer. In some embodiments, the bile duct cancer is proximal bile duct carcinoma or distal bile duct carcinoma. [00179] In some embodiments, the metastasized solid tumor is selected from breast cancer, lung cancer, ovarian cancer, prostate cancer, genitourinary tract cancers,

osteosarcoma, leiomyosarcoma, malignant fibrous histiocytoma, alveolar soft part sarcoma, Ewing's bone sarcomas, melanoma, head and neck cancer, kidney cancer, colorectal cancer, pancreatic cancer, and neuroblastoma. In some embodiments, the metastasized solid tumor is breast cancer. In some embodiments, the metastasized solid tumor is lung cancer. In some embodiments, the metastasized solid tumor is ovarian cancer. In some embodiments, the metastasized solid tumor is prostate cancer. In some embodiments, the metastasized solid tumor is genitourinary tract cancer. In some embodiments, the metastasized solid tumor is osteosarcoma. In some embodiments, the metastasized solid tumor is leiomyosarcoma. In some embodiments, the metastasized solid tumor is malignant fibrous histiocytoma. In some embodiments, the metastasized solid tumor is alveolar soft part sarcoma. In some

embodiments, the metastasized solid tumor is Ewing's bone sarcomas. In some embodiments, the metastasized solid tumor is melanoma. In some embodiments, the metastasized solid tumor is head and neck cancer. In some embodiments, the metastasized solid tumor is kidney cancer. In some embodiments, the metastasized solid tumor is colorectal cancer. In some embodiments, the metastasized solid tumor is pancreatic cancer. In some embodiments, the metastasized solid tumor is neuroblastoma.

[00180] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a metastasized solid tumor in an individual in need thereof which comprises administering a combination of a TEC inhibitor and an

immunomodulating agent. In some embodiments, the TEC inhibitor is a BTK, ITK, TEC, RLK, or BMX inhibitor. In some embodiments, the TEC inhibitor is a Btk inhibitor or an Itk inhibitor. In some embodiments, the TEC inhibitor is a Btk inhibitor. In some embodiments, the Btk inhibitor is ibrutinib. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7- Hl, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TIM3. In some embodiments, the metastasized solid tumor is selected from breast cancer, lung cancer, ovarian cancer, prostate cancer, genitourinary tract cancers, osteosarcoma, leiomyosarcoma, malignant fibrous histiocytoma, alveolar soft part sarcoma, Ewing's bone sarcomas, melanoma, head and neck cancer, kidney cancer, colorectal cancer, pancreatic cancer, and neuroblastoma.

[00181] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a metastasized solid tumor in an individual in need thereof which comprises administering a combination of an Itk inhibitor and an

immunomodulating agent. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7- Hl, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TEVI3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TEVI3. In some embodiments, the metastasized solid tumor is selected from breast cancer, lung cancer, ovarian cancer, prostate cancer, genitourinary tract cancers, osteosarcoma, leiomyosarcoma, malignant fibrous histiocytoma, alveolar soft part sarcoma, Ewing's bone sarcomas, melanoma, head and neck cancer, kidney cancer, colorectal cancer, pancreatic cancer, and neuroblastoma. [00182] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a metastasized solid tumor in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an

immunomodulating agent. In some embodiments, the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA- 056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono

Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), HM71224 (Hanmi Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-0853 (Genentech), or combinations thereof . In some embodiments, the Btk inhibitor is ibrutinib. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, NKG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some

embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the

immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the

immunomodulating agent is an inhibitor of LAG3. In some embodiments, the

immunomodulating agent is an inhibitor of TIM3. In some embodiments, the metastasized solid tumor is selected from breast cancer, lung cancer, ovarian cancer, prostate cancer, genitourinary tract cancers, osteosarcoma, leiomyosarcoma, malignant fibrous histiocytoma, alveolar soft part sarcoma, Ewing's bone sarcomas, melanoma, head and neck cancer, kidney cancer, colorectal cancer, pancreatic cancer, and neuroblastoma.

[00183] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a metastasized solid tumor in an individual in need thereof which comprises administering a combination of ibrutinib and an immunomodulating agent. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the

immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TEVI3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TEVI3. In some embodiments, the metastasized solid tumor is selected from breast cancer, lung cancer, ovarian cancer, prostate cancer, genitourinary tract cancers, osteosarcoma, leiomyosarcoma, malignant fibrous histiocytoma, alveolar soft part sarcoma, Ewing's bone sarcomas, melanoma, head and neck cancer, kidney cancer, colorectal cancer, pancreatic cancer, and neuroblastoma.

[00184] In some embodiments, the metastasized solid tumor is an ibrutinib-resistant solid tumor. In some embodiments, described herein is a method of inducing tumor-specific immunological memory in a metastasized ibrutinib-resistant solid tumor in an individual in need thereof which comprises administering a combination of ibrutinib and an

immunomodulating agent. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7- Hl, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TIM3. In some embodiments, the metastasized ibrutinib-resistant solid tumor is selected from breast cancer, lung cancer, ovarian cancer, prostate cancer, genitourinary tract cancers, osteosarcoma, leiomyosarcoma, malignant fibrous histiocytoma, alveolar soft part sarcoma, Ewing's bone sarcomas, melanoma, head and neck cancer, kidney cancer, colorectal cancer, pancreatic cancer, and neuroblastoma.

[00185] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a metastasized breast cancer in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an

immunomodulating agent. In some embodiments, the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA- 056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono

Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), HM71224 (Hanmi Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-0853 (Genentech), or combinations thereof . In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, ΤΓΜ3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TIM3.

[00186] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a metastasized breast cancer in an individual in need thereof which comprises administering a combination of ibrutinib and an immunomodulating agent. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the

immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TIM3.

[00187] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a metastasized colon cancer in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an immunomodulating agent. In some embodiments, the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA- 056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono

Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), HM71224 (Hanmi Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-0853 (Genentech), or combinations thereof . In some embodiments, the Btk inhibitor is ibrutinib. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, NKG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some

embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the

immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the

immunomodulating agent is an inhibitor of LAG3. In some embodiments, the

immunomodulating agent is an inhibitor of TEVI3.

[00188] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a metastasized colon cancer in an individual in need thereof which comprises administering a combination of ibrutinib and an immunomodulating agent. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the

immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TEVI3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TEVI3.

[00189] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a metastasized lung cancer in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an

immunomodulating agent. In some embodiments, the Btk inhibitor is Ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA- 056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono

Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), HM71224 (Hanmi Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-0853 (Genentech), or combinations thereof . In some embodiments, the Btk inhibitor is ibrutinib. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some

embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the

immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the

immunomodulating agent is an inhibitor of LAG3. In some embodiments, the

immunomodulating agent is an inhibitor of TIM3.

[00190] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a metastasized lung cancer in an individual in need thereof which comprises administering a combination of ibrutinib and an immunomodulating agent. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the

immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TEVI3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TEVI3.

[00191] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a metastasized prostate cancer in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an

immunomodulating agent. In some embodiments, the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA- 056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono

Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), HM71224 (Hanmi Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-0853 (Genentech), or combinations thereof . In some embodiments, the Btk inhibitor is ibrutinib. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, ΤΓΜ4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, NKG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some

embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the

immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the

immunomodulating agent is an inhibitor of LAG3. In some embodiments, the

immunomodulating agent is an inhibitor of ΤΓΜ3.

[00192] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a metastasized prostate cancer in an individual in need thereof which comprises administering a combination of ibrutinib and an immunomodulating agent. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the

immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TIM3.

[00193] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a metastasized pancreatic cancer in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an

immunomodulating agent. In some embodiments, the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA- 056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono

Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), HM71224 (Hanmi Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-0853 (Genentech), or combinations thereof . In some embodiments, the Btk inhibitor is ibrutinib. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, NKG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some

embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the

immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the

immunomodulating agent is an inhibitor of LAG3. In some embodiments, the

immunomodulating agent is an inhibitor of TIM3.

[00194] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a metastasized pancreatic cancer in an individual in need thereof which comprises administering a combination of ibrutinib and an immunomodulating agent. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the

immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TIM3.

[00195] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a metastasized ovarian cancer in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an

immunomodulating agent. In some embodiments, the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA- 056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono

Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), HM71224 (Hanmi Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-0853 (Genentech), or combinations thereof . In some embodiments, the Btk inhibitor is ibrutinib. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDO 1 , ID02, TD02, A2aR, PD-L 1 , PD- 1 , CTLA-4, LAG3 , or TIM3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the

immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the

immunomodulating agent is an inhibitor of LAG3. In some embodiments, the

immunomodulating agent is an inhibitor of TEVI3.

[00196] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a metastasized ovarian cancer in an individual in need thereof which comprises administering a combination of ibrutinib and an immunomodulating agent. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1,

- I l l - LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the

immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TIM3.

[00197] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a metastasized bladder cancer in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an

immunomodulating agent. In some embodiments, the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA- 056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono

Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), HM71224 (Hanmi Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-0853 (Genentech), or combinations thereof . In some embodiments, the Btk inhibitor is ibrutinib. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, NKG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-Ll, PD-1, CTLA-4, LAG3, or TIM3. In some embodiments, the immunomodulating agent is an inhibitor of PD-Ll . In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the

immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the

immunomodulating agent is an inhibitor of LAG3. In some embodiments, the

immunomodulating agent is an inhibitor of TIM3.

[00198] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a metastasized bladder cancer in an individual in need thereof which comprises administering a combination of ibrutinib and an immunomodulating agent. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-Ll, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the

immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-Ll, PD-1, CTLA-4, LAG3, or TEVI3. In some embodiments, the immunomodulating agent is an inhibitor of PD-Ll . In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TEVI3.

[00199] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a metastasized proximal or distal bile duct cancer in an individual in need thereof which comprises administering a combination of a BTK inhibitor and an immunomodulating agent. In some embodiments, the Btk inhibitor is ibrutinib, PCI- 45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL- 263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila

Therapeutics/Celgene Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS- 509744 (Bristol-Myers Squibb), CGI-1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA-056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), HM71224 (Hanmi

Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-0853 (Genentech), or combinations thereof . In some embodiments, the Btk inhibitor is ibrutinib. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7- Hl, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TIM3.

[00200] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a metastasized proximal or distal bile duct cancer in an individual in need thereof which comprises administering a combination of ibrutinib and an immunomodulating agent. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7- Hl, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TEVI3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TEVI3.

[00201] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a metastasized melanoma in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an immunomodulating agent. In some embodiments, the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL- 101/CC-lOl (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila

Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene

Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA- 056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono

Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), HM71224 (Hanmi Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-0853 (Genentech), or combinations thereof . In some embodiments, the BTK inhibitor is ibrutinib. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some

embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the

immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the

immunomodulating agent is an inhibitor of LAG3. In some embodiments, the

immunomodulating agent is an inhibitor of TIM3.

[00202] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a metastasized melanoma in an individual in need thereof which comprises administering a combination of ibrutinib and an immunomodulating agent. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some

embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the

immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the

immunomodulating agent is an inhibitor of LAG3. In some embodiments, the

immunomodulating agent is an inhibitor of TIM3.

Hematologic Cancer

[00203] Disclosed herein, in certain embodiments, is a method of inducing tumor- specific immunological memory in a hematologic cancer in an individual in need thereof which comprises administering a combination of a TEC inhibitor and an immunomodulating agent. In some embodiments, the hematologic cancer is a leukemia, a lymphoma, a myeloma, a non-Hodgkin's lymphoma, a Hodgkin's lymphoma, a T-cell malignancy, or a B-cell malignancy.

[00204] In some embodiments, the hematologic cancer is a T-cell malignancy. In some embodiments, the T-cell malignancy is peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), anaplastic large cell lymphoma, angioimmunoblastic lymphoma, cutaneous T- cell lymphoma, adult T-cell leukemia/lymphoma (ATLL), blastic K-cell lymphoma, enteropathy-type T-cell lymphoma, hematosplenic gamma-delta T-cell lymphoma,

lymphoblastic lymphoma, nasal K/T-cell lymphomas, or treatment-related T-cell

lymphomas.

[00205] In some embodiments, the hematologic cancer is a B-cell proliferative disorder. In some embodiments, the cancer is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high risk CLL, or a non-CLL/SLL lymphoma. In some embodiments, the cancer is follicular lymphoma (FL), diffuse large B-cell lymphoma

(DLBCL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt's lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis. In some embodiments, DLBCL is further divided into subtypes: activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL), germinal center diffuse large B-cell lymphoma (GCB DLBCL), and Double-Hit (DH) DLBCL. In some embodiments, ABC-DLBCL is characterized by a CD79B mutation. In some embodiments, ABC-DLBCL is characterized by a CD79A mutation. In some embodiments, the ABC- DLBCL is characterized by a mutation in MyD88, A20, or a combination thereof. In some embodiments, the cancer is acute or chronic myelogenous (or myeloid) leukemia,

myelodysplastic syndrome, or acute lymphoblastic leukemia.

[00206] In some embodiments, the cancer is diffuse large B-cell lymphoma (DLBCL).

In some embodiments, the cancer is activated B-cell diffuse large B-cell lymphoma (ABC- DLBCL). In some embodiments, the cancer is follicular lymphoma (FL). In some

embodiments, the cancer is multiple myeloma. In some embodiments, the cancer is chronic lymphocytic leukemia (CLL). In some embodiments, the cancer is small lymphocytic lymphoma (SLL). In some embodiments, the cancer is non-CLL/SLL lymphoma. In some embodiments, the cancer is high risk CLL or high risk SLL.

[00207] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a hematologic cancer in an individual in need thereof which comprises administering a combination of a TEC inhibitor and an immunomodulating agent. In some embodiments, the TEC inhibitor is a BTK, ITK, TEC, RLK, or BMX inhibitor. In some embodiments, the TEC inhibitor is a BTK inhibitor or an ITK inhibitor. In some embodiments, the TEC inhibitor is a BTK inhibitor. In some embodiments, the BTK inhibitor is ibrutinib. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the

immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TIM3. In some embodiments, the hematologic cancer is a leukemia, a lymphoma, a myeloma, a non-Hodgkin's lymphoma, a Hodgkin's lymphoma, a T-cell malignancy, or a B-cell malignancy. In some embodiments, the hematologic cancer is a B-cell malignancy. In some embodiments, the B-cell malignancy is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high risk CLL, non-CLL/SLL lymphoma, follicular lymphoma (FL), diffuse large B-cell lymphoma

(DLBCL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt's lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis. In some embodiments, the hematologic cancer is CLL. In some embodiments, the hematologic cancer is SLL. In some embodiments, the hematologic cancer is DLBCL. In some embodiments, the hematologic cancer is mantle cell lymphoma. In some embodiments, the hematologic cancer is FL. In some embodiments, the hematologic cancer is Waldenstrom's macroglobulinemia. In some embodiments, the hematologic cancer is multiple myeloma. In some embodiments, the hematologic cancer is Burkitt's lymphoma.

[00208] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a hematologic cancer in an individual in need thereof which comprises administering a combination of an Itk inhibitor and an immunomodulating agent. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the

immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TEVI3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TEVI3. In some embodiments, the hematologic cancer is a leukemia, a lymphoma, a myeloma, a non-Hodgkin's lymphoma, a Hodgkin's lymphoma, a T-cell malignancy, or a B-cell malignancy. In some embodiments, the hematologic cancer is a B-cell malignancy. In some embodiments, the B-cell malignancy is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high risk CLL, non-CLL/SLL lymphoma, follicular lymphoma (FL), diffuse large B-cell lymphoma

(DLBCL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt's lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis. In some embodiments, the hematologic cancer is CLL. In some embodiments, the hematologic cancer is SLL. In some embodiments, the hematologic cancer is DLBCL. In some embodiments, the hematologic cancer is mantle cell lymphoma. In some embodiments, the hematologic cancer is FL. In some embodiments, the hematologic cancer is Waldenstrom's macroglobulinemia. In some embodiments, the hematologic cancer is multiple myeloma. In some embodiments, the hematologic cancer is Burkitt's lymphoma.

[00209] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a hematologic cancer in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an immunomodulating agent. In some embodiments, the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL- 101/CC-lOl (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila

Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene

Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA- 056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono

Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), HM71224 (Hanmi Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-0853 (Genentech), or combinations thereof . In some embodiments, the BTK inhibitor is ibrutinib. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, ΤΓΜ4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDO 1 , ID02, TD02, A2aR, PD-L 1 , PD- 1 , CTLA-4, LAG3 , or TIM3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the

immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TIM3. In some embodiments, the hematologic cancer is a leukemia, a lymphoma, a myeloma, a non-Hodgkin's lymphoma, a Hodgkin's lymphoma, a T-cell malignancy, or a B-cell malignancy. In some embodiments, the hematologic cancer is a B-cell malignancy. In some embodiments, the B-cell malignancy is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high risk CLL, non-CLL/SLL lymphoma, follicular lymphoma (FL), diffuse large B-cell lymphoma

(DLBCL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt's lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis. In some embodiments, the hematologic cancer is CLL. In some embodiments, the hematologic cancer is SLL. In some embodiments, the hematologic cancer is DLBCL. In some embodiments, the hematologic cancer is mantle cell lymphoma. In some embodiments, the hematologic cancer is FL. In some embodiments, the hematologic cancer is Waldenstrom's macroglobulinemia. In some embodiments, the hematologic cancer is multiple myeloma. In some embodiments, the hematologic cancer is Burkitt's lymphoma.

[00210] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a hematologic cancer in an individual in need thereof which comprises administering a combination of ibrutinib and an immunomodulating agent. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TEVI4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the

immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the

immunomodulating agent is an inhibitor of LAG3. In some embodiments, the

immunomodulating agent is an inhibitor of TIM3. In some embodiments, the hematologic cancer is a leukemia, a lymphoma, a myeloma, a non-Hodgkin's lymphoma, a Hodgkin's lymphoma, a T-cell malignancy, or a B-cell malignancy. In some embodiments, the hematologic cancer is a B-cell malignancy. In some embodiments, the B-cell malignancy is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high risk CLL, non-CLL/SLL lymphoma, follicular lymphoma (FL), diffuse large B-cell lymphoma

(DLBCL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt's lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis. In some embodiments, the hematologic cancer is CLL. In some embodiments, the hematologic cancer is SLL. In some embodiments, the hematologic cancer is DLBCL. In some embodiments, the hematologic cancer is mantle cell lymphoma. In some embodiments, the hematologic cancer is FL. In some embodiments, the hematologic cancer is Waldenstrom's macroglobulinemia. In some embodiments, the hematologic cancer is multiple myeloma. In some embodiments, the hematologic cancer is Burkitt's lymphoma.

[00211] In some embodiments, the hematologic cancer is an ibrutinib-resistant hematologic cancer. In some embodiments, described herein is a method of inducing tumor- specific immunological memory in an ibrutinib-resistant hematologic cancer in an individual in need thereof which comprises administering a combination of ibrutinib and an

immunomodulating agent. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7- Hl, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TEVI4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIRl, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TIM3. In some embodiments, the ibrutinib-resistant hematologic cancer is a leukemia, a lymphoma, a myeloma, a non- Hodgkin's lymphoma, a Hodgkin's lymphoma, a T-cell malignancy, or a B-cell malignancy. In some embodiments, the ibrutinib-resistant hematologic cancer is a B-cell malignancy. In some embodiments, the B-cell malignancy is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high risk CLL, non-CLL/SLL lymphoma, follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt's lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis. In some embodiments, the ibrutinib-resistant hematologic cancer is CLL. In some embodiments, the ibrutinib-resistant hematologic cancer is SLL. In some embodiments, the ibrutinib-resistant hematologic cancer is DLBCL. In some embodiments, the ibrutinib-resistant hematologic cancer is mantle cell lymphoma. In some embodiments, the ibrutinib-resistant hematologic cancer is FL. In some embodiments, the ibrutinib-resistant hematologic cancer is

Waldenstrom's macroglobulinemia. In some embodiments, the ibrutinib-resistant

hematologic cancer is multiple myeloma. In some embodiments, the ibrutinib-resistant hematologic cancer is Burkitt's lymphoma.

[00212] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in CLL in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an immunomodulating agent. In some embodiments, the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene

Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene Corporation), AVL-291/CC- 291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI

Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA-056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486

(Hoffmann-La Roche), HM71224 (Hanmi Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-0853 (Genentech), or combinations thereof . In some embodiments, the Btk inhibitor is ibrutinib. In some embodiments, the immunomodulating agent is an antibody that binds specifically to

Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, ΤΓΜ4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, NKG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some

embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the

immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the

immunomodulating agent is an inhibitor of LAG3. In some embodiments, the

immunomodulating agent is an inhibitor of TIM3.

[00213] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in CLL in an individual in need thereof which comprises administering a combination of ibrutinib and an immunomodulating agent. In some embodiments, the immunomodulating agent is an antibody that binds specifically to

Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, ΤΓΜ4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some

embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the

immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the

immunomodulating agent is an inhibitor of LAG3. In some embodiments, the

immunomodulating agent is an inhibitor of TIM3.

[00214] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in SLL in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an immunomodulating agent. In some embodiments, the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene

Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene Corporation), AVL-291/CC- 291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI

Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA-056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486

(Hoffmann-La Roche), HM71224 (Hanmi Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-0853 (Genentech), or combinations thereof . In some embodiments, the Btk inhibitor is ibrutinib. In some embodiments, the immunomodulating agent is an antibody that binds specifically to

Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some

embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the

immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the

immunomodulating agent is an inhibitor of LAG3. In some embodiments, the

immunomodulating agent is an inhibitor of TIM3.

[00215] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in SLL in an individual in need thereof which comprises administering a combination of ibrutinib and an immunomodulating agent. In some embodiments, the immunomodulating agent is an antibody that binds specifically to

Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some

embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the

immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the

immunomodulating agent is an inhibitor of LAG3. In some embodiments, the

immunomodulating agent is an inhibitor of TIM3.

[00216] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in mantle cell lymphoma in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an immunomodulating agent. In some embodiments, the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL- 101/CC-lOl (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila

Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA- 056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono

Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), HM71224 (Hanmi Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-0853 (Genentech), or combinations thereof . In some embodiments, the BTK inhibitor is ibrutinib. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, ΤΓΜ4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some

embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the

immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the

immunomodulating agent is an inhibitor of LAG3. In some embodiments, the

immunomodulating agent is an inhibitor of TIM3.

[00217] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in mantle cell lymphoma in an individual in need thereof which comprises administering a combination of ibrutinib and an immunomodulating agent. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, ΤΓΜ4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some

embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the

immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the

immunomodulating agent is an inhibitor of LAG3. In some embodiments, the

immunomodulating agent is an inhibitor of TIM3.

[00218] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in DLBCL in an individual in need thereof which comprises administering a combination of a BTK inhibitor and an immunomodulating agent. In some embodiments, the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene

Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene Corporation), AVL-291/CC- 291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI

Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA-056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486

(Hoffmann-La Roche), HM71224 (Hanmi Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-0853 (Genentech), or combinations thereof . In some embodiments, the Btk inhibitor is ibrutinib. In some embodiments, the immunomodulating agent is an antibody that binds specifically to

Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, NKG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some

embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the

immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the

immunomodulating agent is an inhibitor of LAG3. In some embodiments, the

immunomodulating agent is an inhibitor of TIM3. In some embodiments, the DLBCL is ABC-DLBCL, GCB-DLBCL, or DH-DLBCL.

[00219] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in DLBCL in an individual in need thereof which comprises administering a combination of ibrutinib and an immunomodulating agent. In some embodiments, the immunomodulating agent is an antibody that binds specifically to

Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some

embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the

immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the

immunomodulating agent is an inhibitor of LAG3. In some embodiments, the

immunomodulating agent is an inhibitor of TEVI3. In some embodiments, the DLBCL is ABC-DLBCL, GCB-DLBCL, or DH-DLBCL.

[00220] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in Waldenstrom's macroglobulinemia in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an immunomodulating agent. In some embodiments, the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA- 056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono

Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), HM71224 (Hanmi Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-0853 (Genentech), or combinations thereof . In some embodiments, the Btk inhibitor is ibrutinib. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, ΤΓΜ4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some

embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the

immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the

immunomodulating agent is an inhibitor of LAG3. In some embodiments, the

immunomodulating agent is an inhibitor of TIM3.

[00221] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in Waldenstrom's macroglobulinemia in an individual in need thereof which comprises administering a combination of ibrutinib and an

immunomodulating agent. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7- Hl, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, ΤΓΜ4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the

immunomodulating agent is an inhibitor of PD-1. In some embodiments, the

immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the

immunomodulating agent is an inhibitor of LAG3. In some embodiments, the

immunomodulating agent is an inhibitor of TIM3.

[00222] In some embodiments, a cancer is a treatment-naive cancer. In some instances, a treatment-naive cancer is a cancer that has not been treated by a therapy, such as for example by a TEC inhibitor, an immunomodulating agent, and/or by an additional therapeutic agent disclosed elsewhere herein. In some embodiments, a treatment-naive cancer is a hematologic cancer. In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a treatment-naive hematologic cancer in an individual in need thereof which comprises administering a combination of ibrutinib and an

immunomodulating agent. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7- Hl, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TEVI3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TEVI3. In some embodiments, the treatment-naive hematologic cancer is a leukemia, a lymphoma, a myeloma, a non- Hodgkin's lymphoma, a Hodgkin's lymphoma, a T-cell malignancy, or a B-cell malignancy. In some embodiments, the ibrutinib-resistant hematologic cancer is a B-cell malignancy. In some embodiments, the B-cell malignancy is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high risk CLL, non-CLL/SLL lymphoma, follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt's lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis. In some embodiments, the treatment-naive hematologic cancer is CLL. In some embodiments, the treatment-naive hematologic cancer is SLL. In some embodiments, the treatment-naive hematologic cancer is DLBCL. In some embodiments, the treatment-naive hematologic cancer is mantle cell lymphoma. In some embodiments, the treatment-naive hematologic cancer is FL. In some embodiments, the treatment-naive hematologic cancer is

Waldenstrom's macroglobulinemia. In some embodiments, the treatment-naive hematologic cancer is multiple myeloma. In some embodiments, the treatment-naive hematologic cancer is Burkitt's lymphoma.

Relapsed or Refractory Hematologic Cancer

[00223] In some embodiments, the hematologic cancer is a relapsed or refractory hematologic cancer. In some embodiments, the relapsed or refractory hematologic cancer is a leukemia, a lymphoma, a myeloma, a non-Hodgkin's lymphoma, a Hodgkin's lymphoma, T- cell malignancy, or a B-cell malignancy.

[00224] In some embodiments, the relapsed or refractory hematologic cancer is a T- cell malignancy. In some embodiments, the relapsed or refractory T-cell malignancy is peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), anaplastic large cell lymphoma, angioimmunoblastic lymphoma, cutaneous T-cell lymphoma, adult T-cell leukemia/lymphoma (ATLL), blastic K-cell lymphoma, enteropathy -type T-cell lymphoma, hematosplenic gamma-delta T-cell lymphoma, lymphoblastic lymphoma, nasal K/T-cell lymphomas, or treatment-related T-cell lymphomas.

[00225] In some embodiments, the relapsed or refractory hematologic cancer is a B- cell proliferative disorder. In some embodiments, the relapsed or refractory cancer is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high risk CLL, or a non- CLL/SLL lymphoma. In some embodiments, the cancer is follicular lymphoma, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom's

macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt' s lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis. In some embodiments, the relapsed or refractory DLBCL is further divided into subtypes: activated B- cell diffuse large B-cell lymphoma (ABC-DLBCL), germinal center diffuse large B-cell lymphoma (GCB DLBCL), and Double-Hit (DH) DLBCL. In some embodiments, ABC- DLBCL is characterized by a CD79B mutation. In some embodiments, ABC-DLBCL is characterized by a CD79A mutation. In some embodiments, the ABC-DLBCL is

characterized by a mutation in MyD88, A20, or a combination thereof. In some embodiments, the cancer is acute or chronic myelogenous (or myeloid) leukemia, myelodysplastic syndrome, or acute lymphoblastic leukemia.

[00226] In some embodiments, the cancer is relapsed or refractory diffuse large B-cell lymphoma (DLBCL). In some embodiments, the cancer is relapsed or refractory activated B- cell diffuse large B-cell lymphoma (ABC-DLBCL). In some embodiments, the cancer is relapsed or refractory follicular lymphoma (FL). In some embodiments, the cancer is relapsed or refractory multiple myeloma. In some embodiments, the cancer is relapsed or refractory chronic lymphocytic leukemia (CLL). In some embodiments, the cancer is relapsed or refractory small lymphocytic lymphoma (SLL). In some embodiments, the cancer is relapsed or refractory non-CLL/SLL lymphoma. In some embodiments, the cancer is relapsed or refractory high risk CLL or high risk SLL.

[00227] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a relapsed or refractory hematologic cancer in an individual in need thereof which comprises administering a combination of a TEC inhibitor and an immunomodulating agent. In some embodiments, the individual has relapsed or has developed a refractory hematologic cancer to an existing therapy. In some embodiments, the TEC inhibitor is a BTK, ITK, TEC, RLK, or BMX inhibitor. In some embodiments, the TEC inhibitor is a Btk inhibitor or an Itk inhibitor. In some embodiments, the TEC inhibitor is a Btk inhibitor. In some embodiments, the Btk inhibitor is ibrutinib. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD 112, CD 113, CD 137, CD137L, CD 155, CD 160, CD226, CD276, CRT AM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX- 40, OX40L, SLAM, TD02, TIGHT, TLIA, VISTA, VTCNl, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some embodiments, the

immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the

immunomodulating agent is an inhibitor of PD-1. In some embodiments, the

immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the

immunomodulating agent is an inhibitor of LAG3. In some embodiments, the

immunomodulating agent is an inhibitor of TIM3. In some embodiments, the relapsed or refractory hematologic cancer is a leukemia, a lymphoma, a myeloma, a non-Hodgkin's lymphoma, a Hodgkin's lymphoma, a T-cell malignancy, or a B-cell malignancy. In some embodiments, the relapsed or refractory hematologic cancer is a relapsed or refractory B-cell malignancy. In some embodiments, the relapsed or refractory B-cell malignancy is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high risk CLL, non- CLL/SLL lymphoma, follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt's lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B cell prolymphocyte leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis. In some embodiments, the relapsed or refractory hematologic cancer is relapsed or refractory CLL. In some embodiments, the relapsed or refractory hematologic cancer is relapsed or refractory SLL. In some embodiments, the relapsed or refractory hematologic cancer is relapsed or refractory DLBCL. In some embodiments, the relapsed or refractory hematologic cancer is relapsed or refractory mantle cell lymphoma. In some embodiments, the relapsed or refractory hematologic cancer is relapsed or refractory FL. In some embodiments, the relapsed or refractory hematologic cancer is relapsed or refractory Waldenstrom's macroglobulinemia. In some embodiments, the relapsed or refractory hematologic cancer is relapsed or refractory multiple myeloma. In some embodiments, the relapsed or refractory hematologic cancer is relapsed or refractory Burkitt's lymphoma.

[00228] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a relapsed or refractory hematologic cancer in an individual in need thereof which comprises administering a combination of an Itk inhibitor and an immunomodulating agent. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7- Hl, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or ΤΓΜ3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of ΤΓΜ3. In some embodiments, the relapsed or refractory hematologic cancer is a leukemia, a lymphoma, a myeloma, a non- Hodgkin's lymphoma, a Hodgkin's lymphoma, a T-cell malignancy, or a B-cell malignancy. In some embodiments, the relapsed or refractory hematologic cancer is a relapsed or refractory B-cell malignancy. In some embodiments, the relapsed or refractory B-cell malignancy is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high risk CLL, non-CLL/SLL lymphoma, follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt' s lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B- lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis. In some embodiments, the relapsed or refractory hematologic cancer is relapsed or refractory CLL. In some embodiments, the relapsed or refractory hematologic cancer is relapsed or refractory SLL. In some embodiments, the relapsed or refractory hematologic cancer is relapsed or refractory DLBCL. In some embodiments, the relapsed or refractory hematologic cancer is relapsed or refractory mantle cell lymphoma. In some embodiments, the relapsed or refractory hematologic cancer is relapsed or refractory FL. In some embodiments, the relapsed or refractory hematologic cancer is relapsed or refractory Waldenstrom's macroglobulinemia. In some embodiments, the relapsed or refractory hematologic cancer is relapsed or refractory multiple myeloma. In some embodiments, the relapsed or refractory hematologic cancer is relapsed or refractory Burkitt's lymphoma.

[00229] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a relapsed or refractory hematologic cancer in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an immunomodulating agent. In some embodiments, the Btk inhibitor is ibrutinib, PCI- 45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL- 263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila

Therapeutics/Celgene Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene

Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS- 509744 (Bristol-Myers Squibb), CGI-1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA-056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), HM71224 (Hanmi

Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-0853 (Genentech), or combinations thereof . In some embodiments, the Btk inhibitor is ibrutinib. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7- Hl, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TFM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIRl, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TIM3. In some embodiments, the relapsed or refractory hematologic cancer is a leukemia, a lymphoma, a myeloma, a non- Hodgkin's lymphoma, a Hodgkin's lymphoma, a T-cell malignancy, or a B-cell malignancy. In some embodiments, the relapsed or refractory hematologic cancer is a relapsed or refractory B-cell malignancy. In some embodiments, the relapsed or refractory B-cell malignancy is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high risk CLL, non-CLL/SLL lymphoma, follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt' s lymphoma, non-Burkitt high grade B cell lymphoma, primary

mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B- lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis. In some embodiments, the relapsed or refractory hematologic cancer is relapsed or refractory CLL. In some embodiments, the relapsed or refractory hematologic cancer is relapsed or refractory SLL. In some embodiments, the relapsed or refractory hematologic cancer is relapsed or refractory DLBCL. In some embodiments, the relapsed or refractory hematologic cancer is relapsed or refractory mantle cell lymphoma. In some embodiments, the relapsed or refractory hematologic cancer is relapsed or refractory FL. In some embodiments, the relapsed or refractory hematologic cancer is relapsed or refractory Waldenstrom's macroglobulinemia. In some embodiments, the relapsed or refractory hematologic cancer is relapsed or refractory multiple myeloma. In some embodiments, the relapsed or refractory hematologic cancer is relapsed or refractory Burkitt' s lymphoma. [00230] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a relapsed or refractory hematologic cancer in an individual in need thereof which comprises administering a combination of ibrutinib and an immunomodulating agent. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7- Hl, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TEVI3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TEVI3. In some embodiments, the relapsed or refractory hematologic cancer is a leukemia, a lymphoma, a myeloma, a non- Hodgkin's lymphoma, a Hodgkin's lymphoma, a T-cell malignancy, or a B-cell malignancy. In some embodiments, the relapsed or refractory hematologic cancer is a relapsed or refractory B-cell malignancy. In some embodiments, the relapsed or refractory B-cell malignancy is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high risk CLL, non-CLL/SLL lymphoma, follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt' s lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B- lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis. In some embodiments, the relapsed or refractory hematologic cancer is relapsed or refractory CLL. In some embodiments, the relapsed or refractory hematologic cancer is relapsed or refractory SLL. In some embodiments, the relapsed or refractory hematologic cancer is relapsed or refractory DLBCL. In some embodiments, the relapsed or refractory hematologic cancer is relapsed or refractory mantle cell lymphoma. In some embodiments, the relapsed or refractory hematologic cancer is relapsed or refractory FL. In some embodiments, the relapsed or refractory hematologic cancer is relapsed or refractory Waldenstrom's macroglobulinemia. In some embodiments, the relapsed or refractory hematologic cancer is relapsed or refractory multiple myeloma. In some embodiments, the relapsed or refractory hematologic cancer is relapsed or refractory Burkitt's lymphoma.

[00231] In some embodiments, the relapsed or refractory hematologic cancer is a relapsed or refractory ibrutinib-resistant hematologic cancer. In some embodiments, described herein is a method of inducing tumor-specific immunological memory in a relapsed or refractory ibrutinib-resistant hematologic cancer in an individual in need thereof which comprises administering a combination of ibrutinib and an immunomodulating agent. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some

embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the

immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the

immunomodulating agent is an inhibitor of LAG3. In some embodiments, the

immunomodulating agent is an inhibitor of TIM3. In some embodiments, the relapsed or refractory ibrutinib-resistant hematologic cancer is a leukemia, a lymphoma, a myeloma, a non-Hodgkin's lymphoma, a Hodgkin's lymphoma, a T-cell malignancy, or a B-cell malignancy. In some embodiments, the ibrutinib-resistant relapsed or refractory hematologic cancer is a relapsed or refractory B-cell malignancy. In some embodiments, the relapsed or refractory B-cell malignancy is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high risk CLL, non-CLL/SLL lymphoma, follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt' s lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis. In some embodiments, the relapsed or refractory ibrutinib-resistant hematologic cancer is relapsed or refractory CLL. In some embodiments, the relapsed or refractory ibrutinib-resistant hematologic cancer is relapsed or refractory SLL. In some embodiments, the relapsed or refractory ibrutinib-resistant hematologic cancer is relapsed or refractory DLBCL. In some embodiments, the relapsed or refractory ibrutinib-resistant hematologic cancer is relapsed or refractory mantle cell lymphoma. In some embodiments, the relapsed or refractory ibrutinib- resistant hematologic cancer is relapsed or refractory FL. In some embodiments, the relapsed or refractory ibrutinib-resistant hematologic cancer is relapsed or refractory Waldenstrom's macroglobulinemia. In some embodiments, the relapsed or refractory ibrutinib-resistant hematologic cancer is relapsed or refractory multiple myeloma. In some embodiments, the relapsed or refractory ibrutinib-resistant hematologic cancer is relapsed or refractory Burkitt' s lymphoma.

[00232] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a relapsed or refractory CLL in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an

immunomodulating agent. In some embodiments, the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA- 056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono

Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), HM71224 (Hanmi Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-0853 (Genentech), or combinations thereof . In some embodiments, the Btk inhibitor is ibrutinib. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some

embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the

immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the

immunomodulating agent is an inhibitor of LAG3. In some embodiments, the

immunomodulating agent is an inhibitor of TIM3.

[00233] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a relapsed or refractory CLL in an individual in need thereof which comprises administering a combination of ibrutinib and an immunomodulating agent. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the

immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TEVI3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TIM3.

[00234] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a relapsed or refractory SLL in an individual in need thereof which comprises administering a combination of a BTK inhibitor and an

immunomodulating agent. In some embodiments, the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA- 056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono

Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), HM71224 (Hanmi Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-0853 (Genentech), or combinations thereof . In some embodiments, the BTK inhibitor is ibrutinib. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, NKG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some

embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the

immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the

immunomodulating agent is an inhibitor of LAG3. In some embodiments, the

immunomodulating agent is an inhibitor of TIM3. [00235] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a relapsed or refractory SLL in an individual in need thereof which comprises administering a combination of ibrutinib and an immunomodulating agent. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the

immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TEVI3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TEVI3.

[00236] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a relapsed or refractory mantle cell lymphoma in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an immunomodulating agent. In some embodiments, the Btk inhibitor is ibrutinib, PCI- 45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL- 263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila

Therapeutics/Celgene Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene

Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS- 509744 (Bristol-Myers Squibb), CGI-1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA-056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), HM71224 (Hanmi

Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-0853 (Genentech), or combinations thereof . In some embodiments, the Btk inhibitor is ibrutinib. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7- Hl, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TIM3.

[00237] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a relapsed or refractory mantle cell lymphoma in an individual in need thereof which comprises administering a combination of ibrutinib and an immunomodulating agent. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7- Hl, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TEVI3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TIM3.

[00238] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a relapsed or refractory DLBCL in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an

immunomodulating agent. In some embodiments, the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA- 056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono

Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), HM71224 (Hanmi Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-0853 (Genentech), or combinations thereof . In some embodiments, the BTK inhibitor is ibrutinib. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, NKG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some

embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the

immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the

immunomodulating agent is an inhibitor of LAG3. In some embodiments, the

immunomodulating agent is an inhibitor of TEVI3. In some embodiments, the DLBCL is ABC -DLBCL, GCB-DLBCL, or DH-DLBCL. [00239] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a relapsed or refractory DLBCL in an individual in need thereof which comprises administering a combination of ibrutinib and an immunomodulating agent. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the

immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TEVI3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TEVI3. In some embodiments, the DLBCL is ABC-DLBCL, GCB-DLBCL, or DH-DLBCL.

[00240] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a relapsed or refractory Waldenstrom's

macroglobulinemia in an individual in need thereof which comprises administering a combination of a BTK inhibitor and an immunomodulating agent. In some embodiments, the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila

Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene

Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene Corporation), AVL-291/CC- 291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI

Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA-056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486

(Hoffmann-La Roche), HM71224 (Hanmi Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-0853 (Genentech), or combinations thereof . In some embodiments, the Btk inhibitor is ibrutinib. In some embodiments, the immunomodulating agent is an antibody that binds specifically to

Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TLIA, VISTA, VTCNl, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some

embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the

immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the

immunomodulating agent is an inhibitor of LAG3. In some embodiments, the

immunomodulating agent is an inhibitor of TIM3.

[00241] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a relapsed or refractory Waldenstrom's

macroglobulinemia in an individual in need thereof which comprises administering a combination of ibrutinib and an immunomodulating agent. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD 112, CD 113, CD 137, CD137L, CD 155, CD 160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, NKG2A, PS (phosphatidylserine), OX- 40, OX40L, SLAM, TD02, TIGHT, TLIA, VISTA, VTCNl, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some embodiments, the

immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the

immunomodulating agent is an inhibitor of LAG3. In some embodiments, the

immunomodulating agent is an inhibitor of TIM3.

Metastasized Hematologic Cancer

[00242] In some embodiments, the hematologic cancer is a metastasized hematologic cancer. In some embodiments, the metastasized hematologic cancer is a leukemia, a lymphoma, a myeloma, a non-Hodgkin's lymphoma, a Hodgkin's lymphoma, a T-cell malignancy, or a B-cell malignancy.

[00243] In some embodiments, the metastasized hematologic cancer is a T-cell malignancy. In some embodiments, the T-cell malignancy is peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), anaplastic large cell lymphoma, angioimmunoblastic lymphoma, cutaneous T-cell lymphoma, adult T-cell leukemia/lymphoma (ATLL), blastic K-cell lymphoma, enteropathy-type T-cell lymphoma, hematosplenic gamma-delta T-cell lymphoma, lymphoblastic lymphoma, nasal K/T-cell lymphomas, or treatment-related T- cell lymphomas.

[00244] In some embodiments, the metastasized hematologic cancer is a B-cell proliferative disorder. In some embodiments, the metastasized hematologic cancer is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high risk CLL, or a non- CLL/SLL lymphoma. In some embodiments, the metastasized hematologic cancer is follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt' s lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis. In some embodiments, DLBCL is further divided into subtypes: activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL), germinal center diffuse large B-cell lymphoma (GCB DLBCL), and Double-Hit (DH) DLBCL. In some embodiments, ABC-DLBCL is characterized by a CD79B mutation. In some embodiments, ABC-DLBCL is characterized by a CD79A mutation. In some embodiments, the ABC-DLBCL is characterized by a mutation in MyD88, A20, or a combination thereof. In some embodiments, the cancer is acute or chronic myelogenous (or myeloid) leukemia, myelodysplasia syndrome, or acute lymphoblastic leukemia.

[00245] In some embodiments, the metastasized hematologic cancer is diffuse large B- cell lymphoma (DLBCL). In some embodiments, the metastasized hematologic cancer is activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL). In some embodiments, the metastasized hematologic cancer is follicular lymphoma (FL). In some embodiments, the metastasized hematologic cancer is multiple myeloma. In some embodiments, the

metastasized hematologic cancer is chronic lymphocytic leukemia (CLL). In some embodiments, the metastasized hematologic cancer is small lymphocytic lymphoma (SLL). In some embodiments, the metastasized hematologic cancer is non-CLL/SLL lymphoma. In some embodiments, the metastasized hematologic cancer is high risk CLL or high risk SLL.

[00246] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a metastasized hematologic cancer in an individual in need thereof which comprises administering a combination of a TEC inhibitor and an immunomodulating agent. In some embodiments, the TEC inhibitor is a BTK, ITK, TEC, RLK, or BMX inhibitor. In some embodiments, the TEC inhibitor is a Btk inhibitor or an Itk inhibitor. In some embodiments, the TEC inhibitor is a Btk inhibitor. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death- Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS

(phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some

embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the

immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the

immunomodulating agent is an inhibitor of LAG3. In some embodiments, the

immunomodulating agent is an inhibitor of TIM3. In some embodiments, the metastasized hematologic cancer is a leukemia, a lymphoma, a myeloma, a non-Hodgkin's lymphoma, a Hodgkin's lymphoma, a T-cell malignancy, or a B-cell malignancy. In some embodiments, the metastasized hematologic cancer is a metastasized B-cell malignancy. In some

embodiments, the metastasized B-cell malignancy is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high risk CLL, non-CLL/SLL lymphoma, follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt's lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis. In some embodiments, the metastasized hematologic cancer is metastasized CLL. In some

embodiments, the metastasized hematologic cancer is metastasized SLL. In some

embodiments, the metastasized hematologic cancer is metastasized DLBCL. In some embodiments, the metastasized hematologic cancer is metastasized mantle cell lymphoma. In some embodiments, the metastasized hematologic cancer is metastasized FL. In some embodiments, the metastasized hematologic cancer is metastasized Waldenstrom's macroglobulinemia. In some embodiments, the metastasized hematologic cancer is metastasized multiple myeloma. In some embodiments, the metastasized hematologic cancer is metastasized Burkitt's lymphoma.

[00247] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a metastasized hematologic cancer in an individual in need thereof which comprises administering a combination of an Itk inhibitor and an immunomodulating agent. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7- Hl, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TEVI4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TIM3. In some embodiments, the metastasized hematologic cancer is a leukemia, a lymphoma, a myeloma, a non- Hodgkin's lymphoma, a Hodgkin's lymphoma, a T-cell malignancy, or a B-cell malignancy. In some embodiments, the metastasized hematologic cancer is a metastasized B-cell malignancy. In some embodiments, the metastasized B-cell malignancy is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high risk CLL, non- CLL/SLL lymphoma, follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt's lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis. In some embodiments, the metastasized hematologic cancer is metastasized CLL. In some embodiments, the metastasized hematologic cancer is metastasized SLL. In some embodiments, the metastasized hematologic cancer is metastasized DLBCL. In some embodiments, the metastasized hematologic cancer is metastasized mantle cell lymphoma. In some embodiments, the metastasized hematologic cancer is metastasized FL. In some embodiments, the metastasized hematologic cancer is metastasized Waldenstrom's macroglobulinemia. In some embodiments, the metastasized hematologic cancer is metastasized multiple myeloma. In some embodiments, the metastasized hematologic cancer is metastasized Burkitt's lymphoma.

[00248] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a metastasized hematologic cancer in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an immunomodulating agent. In some embodiments, the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA- 056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono

Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), HM71224 (Hanmi Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-0853 (Genentech), or combinations thereof . In some embodiments, the Btk inhibitor is ibrutinib. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, ΤΓΜ4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, NKG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some

embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the

immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the

immunomodulating agent is an inhibitor of LAG3. In some embodiments, the

immunomodulating agent is an inhibitor of TIM3. In some embodiments, the metastasized hematologic cancer is a leukemia, a lymphoma, a myeloma, a non-Hodgkin's lymphoma, a Hodgkin's lymphoma, a T-cell malignancy, or a B-cell malignancy. In some embodiments, the metastasized hematologic cancer is a metastasized B-cell malignancy. In some

embodiments, the metastasized B-cell malignancy is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high risk CLL, non-CLL/SLL lymphoma, follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt's lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis. In some embodiments, the metastasized hematologic cancer is metastasized CLL. In some

embodiments, the metastasized hematologic cancer is metastasized SLL. In some

embodiments, the metastasized hematologic cancer is metastasized DLBCL. In some embodiments, the metastasized hematologic cancer is metastasized mantle cell lymphoma. In some embodiments, the metastasized hematologic cancer is metastasized FL. In some embodiments, the metastasized hematologic cancer is metastasized Waldenstrom's macroglobulinemia. In some embodiments, the metastasized hematologic cancer is metastasized multiple myeloma. In some embodiments, the metastasized hematologic cancer is metastasized Burkitt's lymphoma.

[00249] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a metastasized hematologic cancer in an individual in need thereof which comprises administering a combination of ibrutinib and an

immunomodulating agent. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7- Hl, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or ΤΓΜ3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of ΤΓΜ3. In some embodiments, the metastasized hematologic cancer is a leukemia, a lymphoma, a myeloma, a non- Hodgkin's lymphoma, a Hodgkin's lymphoma, a T-cell malignancy, or a B-cell malignancy. In some embodiments, the metastasized hematologic cancer is a metastasized B-cell malignancy. In some embodiments, the metastasized B-cell malignancy is chronic

lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high risk CLL, non- CLL/SLL lymphoma, follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt's lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis. In some embodiments, the metastasized hematologic cancer is metastasized CLL. In some embodiments, the metastasized hematologic cancer is metastasized SLL. In some embodiments, the metastasized hematologic cancer is metastasized DLBCL. In some embodiments, the metastasized hematologic cancer is metastasized mantle cell lymphoma. In some embodiments, the metastasized hematologic cancer is metastasized FL. In some embodiments, the metastasized hematologic cancer is metastasized Waldenstrom's

macroglobulinemia. In some embodiments, the metastasized hematologic cancer is

metastasized multiple myeloma. In some embodiments, the metastasized hematologic cancer is metastasized Burkitt's lymphoma.

[00250] In some embodiments, a metastasized hematologic cancer is an ibrutinib- resistant hematologic cancer. In some embodiments, described herein is a method of inducing tumor-specific immunological memory in a metastasized ibrutinib-resistant hematologic cancer in an individual in need thereof which comprises administering a combination of ibrutinib and an immunomodulating agent. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIRl, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TLIA, VISTA, VTCNl, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TIM3. In some embodiments, the metastasized ibrutinib-resistant hematologic cancer is a leukemia, a lymphoma, a myeloma, a non-Hodgkin's lymphoma, a Hodgkin's lymphoma, a T-cell malignancy, or a B- cell malignancy. In some embodiments, the metastasized ibrutinib-resistant hematologic cancer is a metastasized B-cell malignancy. In some embodiments, the metastasized B-cell malignancy is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high risk CLL, non-CLL/SLL lymphoma, follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt' s lymphoma, non-Burkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B- lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis. In some embodiments, the metastasized ibrutinib-resistant hematologic cancer is metastasized CLL. In some embodiments, the metastasized ibrutinib- resistant hematologic cancer is metastasized SLL. In some embodiments, the metastasized ibrutinib-resistant hematologic cancer is metastasized DLBCL. In some embodiments, the metastasized ibrutinib-resistant hematologic cancer is metastasized mantle cell lymphoma. In some embodiments, the metastasized ibrutinib-resistant hematologic cancer is metastasized FL. In some embodiments, the metastasized ibrutinib-resistant hematologic cancer is metastasized Waldenstrom's macroglobulinemia. In some embodiments, the metastasized ibrutinib-resistant hematologic cancer is metastasized multiple myeloma. In some embodiments, the metastasized ibrutinib-resistant hematologic cancer is metastasized Burkitt' s lymphoma.

[00251] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a metastasized CLL in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an immunomodulating agent. In some embodiments, the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL- 101/CC-lOl (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila

Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene

Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA- 056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono

Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), HM71224 (Hanmi Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-0853 (Genentech), or combinations thereof . In some embodiments, the BTK inhibitor is ibrutinib. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, ΤΓΜ4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some

embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the

immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the

immunomodulating agent is an inhibitor of LAG3. In some embodiments, the

immunomodulating agent is an inhibitor of TIM3.

[00252] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a metastasized CLL in an individual in need thereof which comprises administering a combination of ibrutinib and an immunomodulating agent. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, ΤΓΜ4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDO 1 , ID02, TD02, A2aR, PD-L 1 , PD- 1 , CTLA-4, LAG3 , or TIM3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the

immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the

immunomodulating agent is an inhibitor of LAG3. In some embodiments, the

immunomodulating agent is an inhibitor of TIM3.

[00253] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a metastasized SLL in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an immunomodulating agent. In some embodiments, the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-101/CC- 101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila

Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene

Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA- 056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono

Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), HM71224 (Hanmi Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-0853 (Genentech), or combinations thereof . In some embodiments, the Btk inhibitor is ibrutinib. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, ΤΓΜ4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the

immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the

immunomodulating agent is an inhibitor of LAG3. In some embodiments, the

immunomodulating agent is an inhibitor of TIM3.

[00254] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a metastasized SLL in an individual in need thereof which comprises administering a combination of ibrutinib and an immunomodulating agent. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some

embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the

immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the

immunomodulating agent is an inhibitor of LAG3. In some embodiments, the

immunomodulating agent is an inhibitor of TIM3.

[00255] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a metastasized mantle cell lymphoma in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an immunomodulating agent. In some embodiments, the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA- 056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono

Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), HM71224 (Hanmi Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-0853 (Genentech), or combinations thereof . In some embodiments, the Btk inhibitor is ibrutinib. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, ΤΓΜ4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some

embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the

immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the

immunomodulating agent is an inhibitor of LAG3. In some embodiments, the

immunomodulating agent is an inhibitor of TIM3.

[00256] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a metastasized mantle cell lymphoma in an individual in need thereof which comprises administering a combination of ibrutinib and an

immunomodulating agent. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7- Hl, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, ΤΓΜ4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCNl, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TIM3.

[00257] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a metastasized DLBCL in an individual in need thereof which comprises administering a combination of a Btk inhibitor and an immunomodulating agent. In some embodiments, the Btk inhibitor is ibrutinib, PCI-45292, PCI-45466, AVL- 101/CC-lOl (Avila Therapeutics/Celgene Corporation), AVL-263/CC-263 (Avila

Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila Therapeutics/Celgene

Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS-509744 (Bristol-Myers Squibb), CGI- 1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA- 056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono

Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), HM71224 (Hanmi Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-0853 (Genentech), or combinations thereof . In some embodiments, the BTK inhibitor is ibrutinib. In some embodiments, the immunomodulating agent is an inhibitor of Programmed Death- Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, 2B4, A2aR, B7H1, B7H3, B7H4, BTLA, CD2, CD27, CD28, CD30, CD40, CD70, CD80, CD86, CD137,CD160, CD226, CD276, DR3, GAL9, GITR, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), KIR, LAIRl, LIGHT, MARCO (macrophage receptor with collageneous structure), PS

(phosphatidylserine), OX- 40, SLAM, TIGHT, VISTA, VTCNl, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the

immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the

immunomodulating agent is an inhibitor of LAG3. In some embodiments, the

immunomodulating agent is an inhibitor of TIM3. In some embodiments, the DLBCL is ABC-DLBCL, GCB-DLBCL, or DH-DLBCL.

[00258] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a metastasized DLBCL in an individual in need thereof which comprises administering a combination of ibrutinib and an immunomodulating agent. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some

embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the

immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the

immunomodulating agent is an inhibitor of LAG3. In some embodiments, the

immunomodulating agent is an inhibitor of TEVI3. In some embodiments, the DLBCL is ABC-DLBCL, GCB-DLBCL, or DH-DLBCL.

[00259] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a metastasized Waldenstrom's macroglobulinemia in an individual in need thereof which comprises administering a combination of a BTK inhibitor and an immunomodulating agent. In some embodiments, the Btk inhibitor is ibrutinib, PCI- 45292, PCI-45466, AVL-lOl/CC-101 (Avila Therapeutics/Celgene Corporation), AVL- 263/CC-263 (Avila Therapeutics/Celgene Corporation), AVL-292/CC-292 (Avila

Therapeutics/Celgene Corporation), AVL-291/CC-291 (Avila Therapeutics/Celgene

Corporation), CNX 774 (Avila Therapeutics), BMS-488516 (Bristol-Myers Squibb), BMS- 509744 (Bristol-Myers Squibb), CGI-1746 (CGI Pharma/Gilead Sciences), CGI-560 (CGI Pharma/Gilead Sciences), CTA-056, GDC-0834 (Genentech), HY-11066 (also, CTK4I7891, HMS3265G21, HMS3265G22, HMS3265H21, HMS3265H22, 439574-61-5, AG-F-54930), ONO-4059 (Ono Pharmaceutical Co., Ltd.), ONO-WG37 (Ono Pharmaceutical Co., Ltd.), PLS-123 (Peking University), RN486 (Hoffmann-La Roche), HM71224 (Hanmi

Pharmaceutical Company Limited), LFM-A13, PRN1008 (Principia), CTP-730 (Concert Pharmaceuticals), GDC-0853 (Genentech), or combinations thereof . In some embodiments, the BTK inhibitor is ibrutinib. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7- Hl, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, ΤΓΜ4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or ΤΓΜ3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of ΤΓΜ3.

[00260] In some embodiments, described herein is a method of inducing tumor- specific immunological memory in a metastasized Waldenstrom's macroglobulinemia in an individual in need thereof which comprises administering a combination of ibrutinib and an immunomodulating agent. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7- Hl, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, ΤΓΜ4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TIM3.

Additional Therapeutic Agents

[00261] In some embodiments, a TEC inhibitor and an immunomodulating agent are administered in combination with an additional therapeutic agent for the treatment of cancer. In some embodiments, the additional therapeutic agent is an anticancer agent for the treatment of a solid tumor. In some embodiments, the additional therapeutic agent is an anticancer agent for the treatment of a hematologic cancer. In some embodiments, the additional anticancer agent is an anticancer agent for the treatment of a B-cell malignancy, such as CLL, SLL, DLBCL, mantle cell lymphoma, or Waldenstrom's macroglobulinemia. In some embodiments, the additional anticancer agent is an anticancer agent for the treatment of a solid tumor such as bladder, breast, colon, pancreatic, lung, prostate, ovarian, proximal or distal bile duct cancer, or melanoma. Non-limiting examples of anticancer agent include chemotherapeutic agents, biologic agents, radiation therapy, thermal therapy, or surgery. In some embodiments, the TEC inhibitor is a BTK, ITK, TEC, RLK, or BMX inhibitor. In some embodiments, the TEC inhibitor is a BTK inhibitor or an ITK inhibitor. In some

embodiments, the TEC inhibitor is a BTK inhibitor. In some embodiments, the Btk inhibitor is ibrutinib. In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, NKG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3.

[00262] In some embodiments, a TEC inhibitor (e.g. Itk inhibitor or Btk inhibitor such as ibrutinib) and an immunomodulating agent are administered in combination with an anticancer agent such as for example irinotecan, cisplatin, carboplatin, methotrexate, etoposide, bleomycin, vinblastine, actinomycin (dactinomycin), cyclophosphamide, ifosfamide, gossyphol, genasense, polyphenol E, Chlorofusin, all trans-retinoic acid (ATRA), bryostatin, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), 5-aza-2'- deoxycytidine, all trans retinoic acid, doxorubicin, vincristine, etoposide, gemcitabine, imatinib (Gleevec®), geldanamycin, 17-N-Allylamino-17-Demethoxygeldanamycin

(17-AAG), flavopiridol, LY294002, bortezomib, trastuzumab, BAY 11-7082, PKC412, or PD 184352, Taxol™, also referred to as "paclitaxel", which is a well-known anti-cancer drug which acts by enhancing and stabilizing microtubule formation, analogs of Taxol™, such as Taxotere™, or a combination thereof.

[00263] In some embodiments, a TEC inhibitor (e.g. Itk inhibitor or Btk inhibitor such as ibrutinib) and an immunomodulating agent are administered in combination with an anticancer agent such as for example inhibitors of mitogen-activated protein kinase signaling, e.g., U0126, PD98059, PD184352, PD0325901, ARRY-142886, SB239063, SP600125, BAY 43-9006, wortmannin, or LY294002; Syk inhibitors; mTOR inhibitors; and antibodies (e.g., rituxan).

[00264] In some embodiments, a TEC inhibitor (e.g. Itk inhibitor or Btk inhibitor such as ibrutinib) and an immunomodulating agent are administered in combination with an anticancer agent such as for example Adriamycin, Dactinomycin, Bleomycin, Vinblastine, Cisplatin, acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; chlorambucil;

cirolemycin; cladribine; crisnatol mesylate; cyclophosphamide; cytarabine; dacarbazine;

daunorubicin hydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin; doxorubicin hydrochloride; droloxifene; droloxifene citrate;

dromostanolone propionate; duazomycin; edatrexate; eflomithine hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine phosphate sodium; etanidazole; etoposide;

etoposide phosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; flurocitabine; fosquidone; fostriecin sodium;

gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; iimofosine; interleukin II (including recombinant interleukin II, or rlL2), interferon alfa-2a; interferon alfa-2b; interferon alfa-nl; interferon alfa-n3; interferon beta-1 a; interferon gamma-1 b; iproplatin; irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium;

metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin;

mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazoie; nogalamycin; ormaplatin; oxisuran; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin;

plomestane; porfimer sodium; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safingol; safingol hydrochloride; semustine; simtrazene; sparfosate sodium; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate;

vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicin hydrochloride.

[00265] In some embodiments, a TEC inhibitor (e.g. Itk inhibitor or Btk inhibitor such as ibrutinib) and an immunomodulating agent are administered in combination with an anticancer agent such as for example 20-epi-l, 25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein- 1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactam derivatives; beta-alethine;

betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene;

bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorlns; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomifene analogues; clotrimazole; collismycin A; collismycin B; combretastatin A4; combretastatin analogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8;

cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone;

didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine; 9- dioxamycin; diphenyl spiromustine; docosanol; dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur; epirubicin; epristeride; estramustine analogue; estrogen agonists; estrogen antagonists; etanidazole;

etoposide phosphate; exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride;

forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate;

galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod; immunostimulant peptides; insulin-like growth factor-1 receptor inhibitor; interferon agonists; interferons;

interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate;

lanreotide; leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon; leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine;

losoxantrone; lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone; mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonal antibody, human chorionic gonadotrophin; monophosphoryl lipid A+myobacterium cell wall sk; mopidamol; multiple drug resistance gene inhibitor; multiple tumor suppressor 1 -based therapy; mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract;

myriaporone; N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip;

naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin;

neridronic acid; neutral endopeptidase; nilutamide; nisamycin; nitric oxide modulators;

nitroxide antioxidant; nitrullyn; 06-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol;

panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium; pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin;

phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin;

piritrexim; placetin A; placetin B; plasminogen activator inhibitor; platinum complex;

platinum compounds; platinum-triamine complex; porfimer sodium; porfiromycin;

prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulator; protein kinase C inhibitor; protein kinase C inhibitors, microalgal;

protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylerie conjugate; raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginone B l; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescence derived inhibitor 1; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen-binding protein; sizofiran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparfosic acid;

spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-cell division inhibitors; stipiamide; stromelysin inhibitors; sulfinosine; superactive vasoactive intestinal peptide antagonist; suradista; suramin; swainsonine; synthetic

glycosaminoglycans; tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; temozolomide;

teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine;

triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors;

tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor; urokinase receptor antagonists; vapreotide; variolin B; vector system, erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer.

[00266] In some embodiments, a TEC inhibitor (e.g. Itk inhibitor or Btk inhibitor such as ibrutinib) and an immunomodulating agent are administered in combination with an anticancer agent such as for example alkylating agents, antimetabolites, natural products, or hormones, e.g., nitrogen mustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil, etc.), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne, etc.), or triazenes (decarbazine, etc.). Examples of antimetabolites include but are not limited to folic acid analog (e.g., methotrexate), or pyrimidine analogs (e.g., Cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin).

[00267] In some embodiments, a TEC inhibitor (e.g. Itk inhibitor or Btk inhibitor such as ibrutinib) and an immunomodulating agent are administered in combination with an anticancer agent such as for example vinca alkaloids (e.g., vinblastin, vincristine),

epipodophyllotoxins (e.g., etoposide), antibiotics (e.g., daunorubicin, doxorubicin,

bleomycin), enzymes (e.g., L-asparaginase), or biological response modifiers (e.g., interferon alpha, IL-2, IL-21).

[00268] In some embodiments, a TEC inhibitor (e.g. Itk inhibitor or Btk inhibitor such as ibrutinib) and an immunomodulating agent are administered in combination with an anticancer agent such as for example nitrogen mustards (e.g., mechloroethamine,

cyclophosphamide, chlorambucil, meiphalan, etc.), ethylenimine and methylmelamines (e.g., hexamethlymelamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne, semustine, streptozocin, etc.), or triazenes (decarbazine, etc.).

Examples of antimetabolites include, but are not limited to folic acid analog (e.g.,

methotrexate), or pyrimidine analogs (e.g., fluorouracil, floxouridine, Cytarabine), purine analogs (e.g., mercaptopurine, thioguanine, pentostatin.

[00269] In some embodiments, a TEC inhibitor (e.g. Itk inhibitor or Btk inhibitor such as ibrutinib) and an immunomodulating agent are administered in combination with an anticancer agent such as for example adrenocorticosteroids (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., diethlystilbestrol, ethinyl estradiol), antiestrogen (e.g., tamoxifen), androgens (e.g., testosterone propionate, fluoxymesterone), antiandrogen (e.g., flutamide), gonadotropin releasing hormone analog (e.g., leuprolide). Other agents for use in the methods and compositions described herein for the treatment or prevention of cancer include platinum coordination complexes (e.g., cisplatin, carboblatin), anthracenedione (e.g., mitoxantrone), substituted urea (e.g., hydroxyurea), methyl hydrazine derivative (e.g., procarbazine), adrenocortical suppressant (e.g., mitotane, aminoglutethimide).

[00270] In some embodiments, a TEC inhibitor (e.g. Itk inhibitor or Btk inhibitor such as ibrutinib) and an immunomodulating agent are administered in combination with an anticancer agent such as for example thrombolytic agents (e.g., alteplase anistreplase, streptokinase, urokinase, or tissue plasminogen activator), heparin, tinzaparin, warfarin, dabigatran (e.g., dabigatran etexilate), factor Xa inhibitors (e.g., fondaparinux, draparinux, rivaroxaban, DX-9065a, otamixaban, LY517717, or YM150), factor Vila inhibitors, ticlopidine, clopidogrel, CS-747 (prasugrel, LY640315), ximelagatran, or BIBR 1048.

[00271] In some embodiments, a TEC inhibitor (e.g. Itk inhibitor or Btk inhibitor such as ibrutinib) and an immunomodulating agent are administered in combination with an anticancer agent such as for example ABVD (adriamycin, bleomycin, vinblastine and dacarbazine), ChlvPP (chlorambucil, vinblastine, procarbazine and prednisolone), Stanford V (mustine, doxorubicin, vinblastine, vincristine, bleomycin, etoposide and steroids),

BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisolone), BEAM (carmustine (BiCNU) etoposide, cytarabine (Ara-C, cytosine arabinoside), and melphalan), CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), R-CHOP (rituximab, doxorubicin, cyclophosphamide, vincristine, and prednisone), EPOCH (etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisone), CVP (cyclophosphamide, vincristine, and prednisone), ICE (ifosfamide- carboplatin-etoposide), R-ACVBP (rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone), DHAP (dexamethasone, high-dose cytarabine, (Ara C), cisplatin), R-DHAP(rituximab, dexamethasone, high-dose cytarabine, (Ara C), cisplatin), ESHAP (etoposide (VP- 16), methyl -prednisolone, and high-dose cytarabine (Ara-C), cisplatin), CDE (cyclophosphamide, doxorubicin and etoposide), Velcade® (bortezomib) plus Doxil® (liposomal doxorubicin), Revlimid® (lenalidomide) plus dexamethasone, and bortezomib plus dexamethasone. [00272] In some embodiments, a TEC inhibitor (e.g. Itk inhibitor or Btk inhibitor such as ibrutinib) and an immunomodulating agent are administered in combination with an anticancer agent such as for example a cancer vaccine. In some instances, a cancer vaccine is a peptide-based vaccine, a nucleic acid based vaccine, a cell-based vaccine, a virus-based or viral fragment based vaccine, an antibody or antibody fragment based vaccine, or an antigen presenting cell (APC) based vaccine (e.g. dendritic cell based vaccine). Exemplary cancer vaccines include Gardasil®, Cervarix®, sipuleucel-T (Provenge®), NeuVax™, HER-2 ICD peptide-based vaccine, HER-2/neu peptide baccine, AdHER2/neu dendritic cell vaccine, HER-2 pulsed DC1 vaccine, Ad-sig-hMUC-l/ecdCD40L fusion protein vaccine, MVX- ONCO-1, hTERT/survivin/CMV multipeptide vaccine, E39, J65, PlOs-PADRE, rV-CEA- Tricom, GVAX®, Lucanix®, HER2 VRP, AVX901, ONT-10, ISA101, ADXS11-001, VGX- 3100, INO-9012, GSK1437173A, BPX-501, AGS-003, IDC-G305, HyperAcute®-Renal (HAR) immunotherapy, Prevenarl3, MAGER-3.A1, NA17.A2, DCVax-Direct, latent membrane protein-2 (LMP2)-loaded dendritic cell vaccine (NCT02115126), HS410-101 (NCT02010203, Heat Biologies), EAU RF 2010-01 (NCT01435356, GSK), 140036

(NCT02015104, Rutgers Cancer Institute of New Jersey), 130016 (NCT01730118, National Cancer Institute), MVX-201101 (NCT02193503, Maxivax SA), ITL-007-ATCR-MBC (NCT01741038, Immunovative Therapies, Limited), CDR0000644921 (NCT00923143, Abramson cancer center of the University of Pennsylvania), SuMo-Sec-01 (NCT00108875, Julius Maximilians Universitaet Hospital), or MCC-15651 (NCT01176474, Medarex, Inc, BMS).

[00273] In some embodiments, a TEC inhibitor (e.g. Btk inhibitor, Itk inhibitor) and an immunomodulating agent are administered in combination with an additional anticancer agent or therapy for the treatment of cancer. In some embodiments, the TEC inhibitor is a Btk inhibitor. In some embodiments, a Btk inhibitor and an immunomodulating agent are administered in combination with an additional anticancer agent or therapy for the treatment of cancer. In some embodiments, the additional therapy for the treatment of cancer is selected from among administration of a chemotherapeutic agent, a biologic agent, radiation therapy, bone marrow transplant or surgery. In some embodiments, the chemotherapeutic agent is selected from among chlorambucil, ifosfamide, doxorubicin, mesalazine, thalidomide, lenalidomide, temsirolimus, everolimus, fludarabine, fostamatinib, paclitaxel, docetaxel, ofatumumab, rituximab, dexamethasone, prednisone, CAL-101, ibritumomab, tositumomab, bortezomib, pentostatin, endostatin, or a combination thereof. In some embodiments, the Btk inhibitor is ibrutinib. [00274] In some embodiments, a TEC inhibitor (e.g. Btk inhibitor or Itk inhibitor) is administered in combination with one or more immunomodulating agents. In some embodiments, a Btk inhibitor (e.g. ibrutinib) is administered in combination with one or more immunomodulating agents. In some embodiments, a Btk inhibitor (e.g. ibrutinib) is administered in combination with at least two immunomodulating agents. In some

embodiments, the immunomodulating agent is an antibody that binds specifically to

Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3.

[00275] In some embodiments, a TEC inhibitor (e.g. Btk inhibitor or Itk inhibitor) and an immunomodulating agent are administered in combination with an additional therapeutic agent for the treatment of a breast cancer. In some embodiments, a Btk inhibitor (e.g.

ibrutinib) and an immunomodulating agent are administered in combination with an additional therapeutic agent for the treatment of a breast cancer. Exemplary therapeutic agents for the treatment of breast cancer include, but are not limited to, ado-trastuzumab emtansine (Kadcyla), anastrozole (Arimidex), capecitabine (Xeloda), cyclophosphamide (Clafen, Cytoxan, Neosar), docetaxel (Taxotere), doxorubicin hydrochloride (Adriamycin PFS, Adriamycin RDF), epirubicin hydrochloride (Ellence), everolimus, exemestane

(Aromasin), fluorouracil (Efudex, Fluoroplex), fulvestrant (Faslodex), gemcitabine hydrochloride (Gemzar), goserelin acetate (Zoladex), ixabepilone (Ixempra), lapatinib ditosylate (Tykerb), letrozole (Femara), megestrol acetate (Megace), methotrexate

(Abitrexate, Folex PFS, Folex, Methotrexate LPF, Mexate-AQ, Mexate), paclitaxel (Taxol), paclitaxel albumin-stabilized nanoparticle formulation (Abraxane), pamidronate disodium (Aredia), pertuzumab (Perjeta), tamoxifen citrate (Nolvadex), toremifene (Fareston), trastuzumab (Herceptin), AC (doxorubicin hydrochloride and cyclophosphamide), AC-T (doxorubicin hydrochloride, cyclophosphamide and paclitaxel), CAF (cyclophosphamide, doxorubicin hydrochloride and fluorouracil), CMF (cyclophosphamide, methotrexate and fluorouracil), FEC (fluorouracil, epirubicin hydrochloride and cyclophosphamide) and TAC (docetaxel, doxorubicin hydrochloride and cyclophosphamide).

[00276] In some embodiments, ibrutinib and an immunomodulating agent are administered in combination with ado-trastuzumab emtansine (Kadcyla), anastrozole

(Arimidex), capecitabine (Xeloda), cyclophosphamide (Clafen, Cytoxan, Neosar), docetaxel (Taxotere), doxorubicin hydrochloride (Adriamycin PFS, Adriamycin RDF), epirubicin hydrochloride (Ellence), everolimus, exemestane (Aromasin), fluorouracil (Efudex,

Fluoroplex), fulvestrant (Faslodex), gemcitabine hydrochloride (Gemzar), goserelin acetate (Zoladex), ixabepilone (Ixempra), lapatinib ditosylate (Tykerb), letrozole (Femara), megestrol acetate (Megace), methotrexate (Abitrexate, Folex PFS, Folex, Methotrexate LPF, Mexate-AQ, Mexate), paclitaxel (Taxol), paclitaxel albumin-stabilized nanoparticle formulation (Abraxane), pamidronate disodium (Aredia), pertuzumab (Perjeta), tamoxifen citrate (Nolvadex), toremifene (Fareston), trastuzumab (Herceptin), AC (doxorubicin hydrochloride and cyclophosphamide), AC-T (doxorubicin hydrochloride, cyclophosphamide and paclitaxel), CAF (cyclophosphamide, doxorubicin hydrochloride and fluorouracil), CMF (cyclophosphamide, methotrexate and fluorouracil), FEC (fluorouracil, epirubicin

hydrochloride and cyclophosphamide) or TAC (docetaxel, doxorubicin hydrochloride and cyclophosphamide) for the treatment of a breast cancer. In some embodiments, ibrutinib and an immunomodulating agent are administered sequentially, simultaneously, or intermittently with the additional therapeutic agent for the treatment of a breast cancer.

[00277] In some embodiments, a TEC inhibitor (e.g. Btk inhibitor or Itk inhibitor) and an immunomodulating agent are administered in combination with an additional therapeutic agent for the treatment of a colon cancer. In some embodiments, a Btk inhibitor (e.g.

ibrutinib) and an immunomodulating agent are administered in combination with an additional therapeutic agent for the treatment of a colon cancer. Exemplary therapeutic agents for the treatment of colon cancer include, but are not limited to, capecitabine (e.g. Xeloda), cetuximab (e.g. Erbitux), bevacizumab (e.g. Avastin), fluorouracil (e.g. Adrucil, Efudex, Fluoroplex), irinotecan hydrochloride (e.g. Camptosar), leucovorin calcium (e.g.

Wellcovorin), oxaliplatin (e.g. Eloxatin), panitumumab (e.g. Vectibix), regorafenib (e.g.

Stivarga), ziv-aflibercept (e.g. Zaltrap), CAPOX (capecitabine and oxaliplatin), FOLFIRI (leucovorin calcium, fluorouracil, and irinotecan hydrochloride), FOLFIRI-BEVACIZUMAB, FOLFIRI-CETUXIMAB, FOLFOX (leucovorin calcium, fluorouracil, and oxaliplatin), or XELOX (capecitabine and oxaliplatin). [00278] In some embodiments, ibrutinib and an immunomodulating agent are administered in combination with capecitabine (e.g. Xeloda), cetuximab (e.g. Erbitux), bevacizumab (e.g. Avastin), fluorouracil (e.g. Adrucil, Efudex, Fluoroplex), irinotecan hydrochloride (e.g. Camptosar), leucovorin calcium (e.g. Wellcovorin), oxaliplatin (e.g.

Eloxatin), panitumumab (e.g. Vectibix), regorafenib (e.g. Stivarga), ziv-aflibercept (e.g.

Zaltrap), CAPOX (capecitabine and oxaliplatin), FOLFIRI (leucovorin calcium, fluorouracil, and irinotecan hydrochloride), FOLFIRI-BEVACIZUMAB, FOLFIRI-CETUXEVIAB, FOLFOX (leucovorin calcium, fluorouracil, and oxaliplatin), or XELOX (capecitabine and oxaliplatin) for the treatment of a colon cancer. In some embodiments, ibrutinib and an immunomodulating agent are administered sequentially, simultaneously, or intermittently with the additional therapeutic agent for the treatment of a colon cancer.

[00279] In some embodiments, a TEC inhibitor (e.g. Btk inhibitor or Itk inhibitor) and an immunomodulating agent are administered in combination with an additional therapeutic agent for the treatment of a bladder cancer. In some embodiments, a Btk inhibitor (e.g.

ibrutinib) and an immunomodulating agent are administered in combination with an additional therapeutic agent for the treatment of a bladder cancer. Exemplary therapeutic agents for the treatment of bladder cancer include, but are not limited to, doxorubicin hydrochloride (Adriamycin PFS/RDF), cisplatin, mitomycin, fluorouracil, gemcitabine, methotrexate, vinblastine, carboplatin, paclitaxel, docetaxel, thiotepa (Thioplex, Tepadina), immunotherapeutic agents (e.g. Bacille Calmette-Guerin, interferon alfa-2b), and radiation therapeutic agents.

[00280] In some embodiments, ibrutinib and an immunomodulating agent are administered in combination with doxorubicin hydrochloride (Adriamycin PFS/RDF), cisplatin, mitomycin, fluorouracil, gemcitabine, methotrexate, vinblastine, carboplatin, paclitaxel, docetaxel, thiotepa (Thioplex, Tepadina), immunotherapeutic agents (e.g. Bacille Calmette-Guerin, interferon alfa-2b), and radiation therapeutic agents. In some embodiments, ibrutinib and an immunomodulating agent are administered sequentially, simultaneously, or intermittently with the additional therapeutic agent for the treatment of a bladder cancer.

[00281] In some embodiments, a TEC inhibitor (e.g. Btk inhibitor or Itk inhibitor) and an immunomodulating agent are administered in combination with an additional therapeutic agent for the treatment of a colon cancer. In some embodiments, a Btk inhibitor (e.g.

ibrutinib) and an immunomodulating agent are administered in combination with an additional therapeutic agent for the treatment of a colon cancer. Exemplary therapeutic agents for the treatment of colon cancer include, but are not limited to, fluorouracil (Adrucil), bevacizumab (Avastin), irinotecan hydrochloride (Camptosar), capecitabine, cetuximab, Efudex, oxaliplatin (Eloxatin), Erbutix, Fluoroplex, leucovorin calcium (Wellcovorin), panitumamab (Vectibix), regorafenib (Stivarga), ziv-aflibercept, CAPOX, FOLFIRI,

FOLFOX, and XELOX.

[00282] In some embodiments, ibrutinib and an immunomodulating agent are administered in combination with fluorouracil (Adrucil), bevacizumab (Avastin), irinotecan hydrochloride (Camptosar), capecitabine, cetuximab, Efudex, oxaliplatin (Eloxatin), Erbutix, Fluoroplex, leucovorin calcium (Wellcovorin), panitumamab (Vectibix), regorafenib

(Stivarga), ziv-aflibercept, CAPOX, FOLFIRI, FOLFOX, and XELOX. In some

embodiments, ibrutinib and an immunomodulating agent are administered sequentially, simultaneously, or intermittently with the additional therapeutic agent for the treatment of a colon cancer.

[00283] In some embodiments, a TEC inhibitor (e.g. Btk inhibitor or Itk inhibitor) and an immunomodulating agent are administered in combination with an additional therapeutic agent for the treatment of a lung cancer. In some embodiments, a Btk inhibitor (e.g. ibrutinib) and an immunomodulating agent are administered in combination with an additional therapeutic agent for the treatment of a lung cancer. Exemplary therapeutic agents for the treatment of lung cancer include, but are not limited to, Adriamycin IV, Rheumatrex,

Mustargen, methotrexate (Abitrexate), Abraxane, afatinib dimaleate (Gilotrif), pemetrexed disodium (Alimta), bevacixumab, carboplatin, cisplatin, crizotinib, erlotinib hydrochloride, Etopophos (etoposide phosphate), Folex, Folex PFS, gefitinib (Iressa), gemcitabine hydrochloride (Gemzar), topotecan hydrochloride (Hycamtin), Methotrexate LPF, Mexate, Mexate-AQ, paclitaxel, Paraplat, Paraplatin, Platinol, Platinol-AQ, Tarceva, Taxol, Xalkori, Toposar, VePesid and MPDL3280A.

[00284] In some embodiments, ibrutinib and an immunomodulating agent are administered in combination with Adriamycin IV, Rheumatrex, Mustargen, methotrexate (Abitrexate), Abraxane, afatinib dimaleate (Gilotrif), pemetrexed disodium (Alimta), bevacixumab, carboplatin, cisplatin, crizotinib, erlotinib hydrochloride, Etopophos (etoposide phosphate), Folex, Folex PFS, gefitinib (Iressa), gemcitabine hydrochloride (Gemzar), topotecan hydrochloride (Hycamtin), Methotrexate LPF, Mexate, Mexate-AQ, paclitaxel, Paraplat, Paraplatin, Platinol, Platinol-AQ, Tarceva, Taxol, Xalkori, Toposar, VePesid and MPDL3280A. In some embodiments, ibrutinib and an immunomodulating agent are administered sequentially, simultaneously, or intermittently with the additional therapeutic agent for the treatment of a lung cancer. [00285] In some embodiments, a TEC inhibitor (e.g. Btk inhibitor or Itk inhibitor) and an immunomodulating agent are administered in combination with an additional therapeutic agent for the treatment of an ovarian cancer. In some embodiments, a Btk inhibitor (e.g. ibrutinib) and an immunomodulating agent are administered in combination with an additional therapeutic agent for the treatment of an ovarian cancer. Exemplary therapeutic agents for the treatment of ovarian cancer include, but are not limited to, doxorubicin hydrochloride (Adriamycin PFS/RDF), carboplatin, cyclophosphamide (Clafen), cisplatin, Cytoxan, Dox-SL, DOXIL, doxorubicin hydrochloride liposome (Evacet), gemcitabine hydrochloride (Gemzar), topotecan hydrochloride (Hycamtin), Neosar, Paclitaxel, Paraplat, Paraplatin, Platinol, Platinol-AQ, Taxol and BEP.

[00286] In some embodiments, ibrutinib and an immunomodulating agent are administered in combination with doxorubicin hydrochloride (Adriamycin PFS/RDF), carboplatin, cyclophosphamide (Clafen), cisplatin, Cytoxan, Dox-SL, DOXIL, doxorubicin hydrochloride liposome (Evacet), gemcitabine hydrochloride (Gemzar), topotecan hydrochloride (Hycamtin), Neosar, Paclitaxel, Paraplat, Paraplatin, Platinol, Platinol-AQ, Taxol and BEP. In some embodiments, ibrutinib and an immunomodulating agent are administered sequentially, simultaneously, or intermittently with the additional therapeutic agent for the treatment of an ovarian cancer.

[00287] In some embodiments, a TEC inhibitor (e.g. Btk inhibitor or Itk inhibitor) and an immunomodulating agent are administered in combination with an additional therapeutic agent for the treatment of a pancreatic cancer. In some embodiments, a Btk inhibitor (e.g. ibrutinib) and an immunomodulating agent are administered in combination with an additional therapeutic agent for the treatment of a pancreatic cancer. Exemplary therapeutic agents for the treatment of pancreatic cancer include, but are not limited to, Adriamycin PFS IV, Adrucil, Efudex, erlotinib hydrochloride, Fluoroplex, fluorouracil, gemcitabine hydrochloride (Gemzar), mitomycin C, Tarceva, Oxaliplatin paclitaxel-protein bound IV, and capecitabine.

[00288] In some embodiments, ibrutinib and an immunomodulating agent are administered in combination with Adriamycin PFS IV, Adrucil, Efudex, erlotinib

hydrochloride, Fluoroplex, fluorouracil, gemcitabine hydrochloride (Gemzar), mitomycin C, Tarceva, Oxaliplatin paclitaxel-protein bound IV, and capecitabine. In some embodiments, ibrutinib and an immunomodulating agent are administered sequentially, simultaneously, or intermittently with the additional therapeutic agent for the treatment of a pancreatic cancer. [00289] In some embodiments, a TEC inhibitor (e.g. Btk inhibitor or Itk inhibitor) and an immunomodulating agent are administered in combination with an additional therapeutic agent for the treatment of a prostate cancer. In some embodiments, a Btk inhibitor (e.g.

ibrutinib) and an immunomodulating agent are administered in combination with an additional therapeutic agent for the treatment of a prostate cancer. Exemplary therapeutic agents for the treatment of prostate cancer include, but are not limited to, abiraterone acetate, cabazitaxel, degarelix, docetaxel, enzalutamide, leuprolide acetate, prednisone, denosumab, sipuleucel-T, abraxane and gemzar, and radium 223 dichloride.

[00290] In some embodiments, ibrutinib and an immunomodulating agent are administered in combination with abiraterone acetate, cabazitaxel, degarelix, docetaxel, enzalutamide, leuprolide acetate, prednisone, denosumab, sipuleucel-T, abraxane and gemzar, and radium 223 dichloride. In some embodiments, ibrutinib and an immunomodulating agent are administered sequentially, simultaneously, or intermittently with the additional therapeutic agent for the treatment of a prostate cancer.

[00291] In some embodiments, a TEC inhibitor (e.g. Btk inhibitor or Itk inhibitor) and an immunomodulating agent are administered in combination with an additional therapeutic agent for the treatment of a proximal or distal bile duct cancer. In some embodiments, a Btk inhibitor (e.g. ibrutinib) and an immunomodulating agent are administered in combination with an additional therapeutic agent for the treatment of a proximal or distal bile duct cancer. Exemplary therapeutic agents for the treatment of proximal or distal bile duct cancer include, but are not limited to, cisplatin, gemcitabine, fluorouracil, and doxorubicin.

[00292] In some embodiments, ibrutinib and an immunomodulating agent are administered in combination with cisplatin, gemcitabine, fluorouracil, and doxorubicin. In some embodiments, ibrutinib and an immunomodulating agent are administered sequentially, simultaneously, or intermittently with the additional therapeutic agent for the treatment of a proximal or distal bile duct cancer.

[00293] In some embodiments, a TEC inhibitor (e.g. Btk inhibitor or Itk inhibitor) and an immunomodulating agent are administered in combination with an additional therapeutic agent for the treatment of CLL. In some embodiments, a Btk inhibitor (e.g. ibrutinib) and an immunomodulating agent are administered in combination with an additional therapeutic agent for the treatment of CLL. Exemplary therapeutic agents for the treatment of CLL include, but are not limited to, alemtuzumab (e.g. Campath), bendamustine hydrochloride (e.g. Treanda), chlorambucil (e.g. Ambochlorin, Amboclorin, Leukeran, Linfolizin), cyclophosphamide (e.g. Clafen, Cytoxan, Neosar), fludarabine phosphate (e.g. Fludara), idelalisib (e.g. Zydelig), mechlorethamine hydrochloride (e.g. Mustargen), obinutuzumab (e.g. Gazyva), ofatumumab (e.g. Arzerra), prednisone, rituximab (e.g. Rituxan), chlorambucil- prednisone, R-CHOP, PCR (pentostatin, cyclophosphamide, rituximab), FR (fludarabine, rituximab), FCR (fludarabine, cyclophosphamide, ritusimab), BR (bendamustine, rituximab), and CVP (cyclophosphamide, vincristine sulfate, prednisone).

[00294] In some embodiments, ibrutinib and an immunomodulating agent are administered in combination with alemtuzumab (e.g. Campath), bendamustine hydrochloride (e.g. Treanda), chlorambucil (e.g. Ambochlorin, Amboclorin, Leukeran, Linfolizin), cyclophosphamide (e.g. Clafen, Cytoxan, Neosar), fludarabine phosphate (e.g. Fludara), idelalisib (e.g. Zydelig), mechlorethamine hydrochloride (e.g. Mustargen), obinutuzumab (e.g. Gazyva), ofatumumab (e.g. Arzerra), prednisone, rituximab (e.g. Rituxan), chlorambucil- prednisone, R-CHOP, PCR (pentostatin, cyclophosphamide, rituximab), FR (fludarabine, rituximab), FCR (fludarabine, cyclophosphamide, ritusimab), BR (bendamustine, rituximab), and CVP (cyclophosphamide, vincristine sulfate, prednisone). In some embodiments, ibrutinib and an immunomodulating agent are administered sequentially, simultaneously, or intermittently with the additional therapeutic agent for the treatment of CLL.

[00295] In some embodiments, a TEC inhibitor (e.g. Btk inhibitor or Itk inhibitor) and an immunomodulating agent are administered in combination with an additional therapeutic agent for the treatment of SLL. In some embodiments, a Btk inhibitor (e.g. ibrutinib) and an immunomodulating agent are administered in combination with an additional therapeutic agent for the treatment of SLL. Exemplary therapeutic agents for the treatment of SLL include, but are not limited to, alemtuzumab (e.g. Campath), bendamustine hydrochloride (e.g. Treanda), chlorambucil (e.g. Ambochlorin, Amboclorin, Leukeran, Linfolizin), cyclophosphamide (e.g. Clafen, Cytoxan, Neosar), fludarabine phosphate (e.g. Fludara), idelalisib (e.g. Zydelig), mechlorethamine hydrochloride (e.g. Mustargen), obinutuzumab (e.g. Gazyva), ofatumumab (e.g. Arzerra), prednisone, rituximab (e.g. Rituxan), chlorambucil- prednisone, R-CHOP, PCR (pentostatin, cyclophosphamide, rituximab), FR (fludarabine, rituximab), FCR (fludarabine, cyclophosphamide, ritusimab), BR (bendamustine, rituximab), and CVP (cyclophosphamide, vincristine sulfate, prednisone).

[00296] In some embodiments, ibrutinib and an immunomodulating agent are administered in combination with alemtuzumab (e.g. Campath), bendamustine hydrochloride (e.g. Treanda), chlorambucil (e.g. Ambochlorin, Amboclorin, Leukeran, Linfolizin), cyclophosphamide (e.g. Clafen, Cytoxan, Neosar), fludarabine phosphate (e.g. Fludara), idelalisib (e.g. Zydelig), mechlorethamine hydrochloride (e.g. Mustargen), obinutuzumab (e.g. Gazyva), ofatumumab (e.g. Arzerra), prednisone, rituximab (e.g. Rituxan), chlorambucil- prednisone, R-CHOP, PCR (pentostatin, cyclophosphamide, rituximab), FR (fludarabine, rituximab), FCR (fludarabine, cyclophosphamide, ritusimab), BR (bendamustine, rituximab), and CVP (cyclophosphamide, vincristine sulfate, prednisone). In some embodiments, ibrutinib and an immunomodulating agent are administered sequentially, simultaneously, or intermittently with the additional therapeutic agent for the treatment of SLL.

[00297] In some embodiments, a TEC inhibitor (e.g. Btk inhibitor or Itk inhibitor) and an immunomodulating agent are administered in combination with an additional therapeutic agent for the treatment of DLBCL. In some embodiments, a Btk inhibitor (e.g. ibrutinib) and an immunomodulating agent are administered in combination with an additional therapeutic agent for the treatment of DLBCL. Exemplary therapeutic agents for the treatment of DLBCL include, but are not limited to, R-CHOP, rituximab, EPOCH, lenalidomide, cisplatin, cytarabine, dexamethasone, ICE (ifosfamide, carboplatin, etoposide), GDP (gemcitabine, dexamethasone, cisplatin), GEM-P (gemcitabine, methylprednisolone, cisplatin), R+GEMOX (rituximab, gemcitabine, oxaliplatin), ESHAP (etoposide, methylprednisolone, cisplatin, cytarabine), DHAP (dexamethasone, cytarabine, cisplatin), R-DHAP, R-DHAP-VFM-DHAP, DHAP-VIM-DHAP, GV (gemcitabine, vinorelbine), GVP (gemcitabine, vinorelbine, prednisone), ViGePP ( vinorelbine, gemcitabine, procarbazine, prednisone), IEV (ifosfamide, etoposide, epirubicin), MINE (ifosfamide, etoposide, mitoxantrone), IV AD (ifosfamide, etoposide, cytarabine, dexamethasone), and Mini-BEAM (busulfan, etoposide, cytarabine, melphalan).

[00298] In some embodiments, ibrutinib and an immunomodulating agent are administered in combination with R-CHOP, rituximab, EPOCH, lenalidomide, cisplatin, cytarabine, dexamethasone, ICE (ifosfamide, carboplatin, etoposide), GDP (gemcitabine, dexamethasone, cisplatin), GEM-P (gemcitabine, methylprednisolone, cisplatin), R+GEMOX (rituximab, gemcitabine, oxaliplatin), ESHAP (etoposide, methylprednisolone, cisplatin, cytarabine), DHAP (dexamethasone, cytarabine, cisplatin), R-DHAP, R-DHAP-VFM-DHAP, DHAP-VIM-DHAP, GV (gemcitabine, vinorelbine), GVP (gemcitabine, vinorelbine, prednisone), ViGePP ( vinorelbine, gemcitabine, procarbazine, prednisone), IEV (ifosfamide, etoposide, epirubicin), MFNE (ifosfamide, etoposide, mitoxantrone), IV AD (ifosfamide, etoposide, cytarabine, dexamethasone), and Mini-BEAM (busulfan, etoposide, cytarabine, melphalan). In some embodiments, ibrutinib and an immunomodulating agent are

administered sequentially, simultaneously, or intermittently with the additional therapeutic agent for the treatment of DLBCL. [00299] In some embodiments, a TEC inhibitor (e.g. Btk inhibitor or Itk inhibitor) and an immunomodulating agent are administered in combination with an additional therapeutic agent for the treatment of mantle cell lymphoma. In some embodiments, a Btk inhibitor (e.g. ibrutinib) and an immunomodulating agent are administered in combination with an additional therapeutic agent for the treatment of mantle cell lymphoma. Exemplary therapeutic agents for the treatment of mantle cell lymphoma include, but are not limited to, CHOP, R-CHOP, CVP (cyclophosphamide, vincristin, prednisolone), fludarabine, cyclophosphamide, chlorambucil, dexamethasone, methylprednisolone, lenalidomide, idelalisib (GS-1101), vorinostat (Zolinza), ofatumumab (Arzerra), everolimus (Afinitor), panobinostat, and temsirolimus (Torisel).

[00300] In some embodiments, ibrutinib and an immunomodulating agent are administered in combination with CHOP, R-CHOP, CVP (cyclophosphamide, vincristin, prednisolone), fludarabine, cyclophosphamide, chlorambucil, dexamethasone,

methylprednisolone, lenalidomide, idelalisib (GS-1101), vorinostat (Zolinza), ofatumumab (Arzerra), everolimus (Afinitor), panobinostat, and temsirolimus (Torisel). In some embodiments, ibrutinib and an immunomodulating agent are administered sequentially, simultaneously, or intermittently with the additional therapeutic agent for the treatment of mantle cell lymphoma.

[00301] In some embodiments, a TEC inhibitor (e.g. Btk inhibitor or Itk inhibitor) and an immunomodulating agent are administered in combination with an additional therapeutic agent for the treatment of Waldenstrom's macroglobulinemia. In some embodiments, a Btk inhibitor (e.g. ibrutinib) and an immunomodulating agent are administered in combination with an additional therapeutic agent for the treatment of Waldenstrom's macroglobulinemia. Exemplary therapeutic agents for the treatment of Waldenstrom's macroglobulinemia include, but are not limited to, chlorambucil, cyclophosphamide, fludarabine, cladribine, rituximab, prednisone, melphalan, 2-chlorodeoxyadenosine, interferon alfa, and interferon gamma.

[00302] In some embodiments, ibrutinib and an immunomodulating agent are administered in combination with chlorambucil, cyclophosphamide, fludarabine, cladribine, rituximab, prednisone, melphalan, 2-chlorodeoxyadenosine, interferon alfa, and interferon gamma. In some embodiments, ibrutinib and an immunomodulating agent are administered sequentially, simultaneously, or intermittently with the additional therapeutic agent for the treatment of Waldenstrom's macroglobulinemia. [00303] Disclosed herein, in some embodiments, are methods including monitoring of treatment methods by analysis of a biomarker. In some embodiments, the expression of a biomarker, the expression level of a biomarker, mutations in a biomarker, or the presence of a biomarker is assayed in a patient receiving the treatment. In some embodiments, the biomarker is ΠΤΝΓγ and an increase in IFNy is indicative of tumor specific immunological memory. In some embodiments, the biomarker is an increase in tumor infiltration by Ki67 ⁺ / IFNy CD4 ⁺ and CD8 ⁺ T cells. In some embodiments, the biomarker is compared to a control biomarker. In some embodiments, the therapeutic regimen is a combination of a TEC inhibitor and an immunomodulating agent. In some embodiments, the biomarker is analyzed prior, during, and/or post administration of a combination of a TEC inhibitor and an immunomodulating agent. In some embodiments, the TEC inhibitor is a Btk inhibitor or an Itk inhibitor. In some embodiments, the TEC inhibitor is a Btk inhibitor. In some

embodiments, the biomarker is analyzed prior, during, and/or post administration of a combination of a Btk inhibitor and an immunomodulating agent. In some embodiments, the Btk inhibitor is ibrutinib. In some embodiments, the biomarker is analyzed prior, during, and/or post administration of a combination of ibrutinib and an immunomodulating agent. In some embodiments, the biomarker is analyzed prior, during, and/or post administration of a combination of a Btk inhibitor (e.g. ibrutinib), an immunomodulating agent, and an additional therapeutic agent.

[00304] In some embodiments, administration of a combination of a Btk inhibitor (e.g. ibrutinib) and an immunomodulating agent increases the expression of one or more biomarkers in a subject. In some embodiments, administration of a combination of a Btk inhibitor (e.g. ibrutinib) and an immunomodulating agent increases the expression of IFN-γ.

[00305] In some embodiments, the biomarker is VEGF. In some embodiments, methods of selecting a patient for combination therapy are provided. The method comprises determining the amount of VEGF in a patient sample. In some embodiments, the amount of VEGF is determined prior the administration of the combination therapy. In some

embodiments, the amount of VEGF is compared to a control. In some embodiments, if the amount of VEGF in the patient sample is greater than the control, then the patient is selected for combination therapy. In some embodiments, the combination therapy comprises ibrutinib and a CTLA-4 inhibitor.

Pharmaceutical Combinations/Formulations [00306] Disclosed herein, in certain embodiments, are pharmaceutical combinations and/or compositions that comprise (a) a Btk inhibitor and an immunomodulating agent, and (b) a pharmaceutically-acceptable excipient. In some embodiments, the Btk inhibitor is ibrutinib. In some embodiments, the combination provides a synergistic therapeutic effect compared to administration of ibrutinib or the second anticancer agent alone. In some instances, the combination provides an additive therapeutic effect compared to administration of ibrutinib or the second anticancer agent alone. In some instances, the combination provides an antagonistic effect compared to administration of ibrutinib or the second anticancer agent alone. In some instances, the combination sensitizes the cancer (e.g. solid tumors, hematologic cancers) to the Btk inhibitor. In some instances, the combination sensitizes the cancer (e.g. solid tumors, hematologic cancers) to the immunomodulating agent. In some instances, the combination sensitizes the cancer (e.g. solid tumors, hematologic cancers) to both the Btk inhibitor and the immunomodulating agent. In some instances, the combination further comprises an additional anticancer agent. In some instances, the combination of a Btk inhibitor, an immunomodulating agent, and an additional anticancer agent provides a synergistic therapeutic effect, or an additive therapeutic effect compared to administrations of the Btk inhibitor, immunomodulating agent, or the additional anticancer agent alone or in dual combinations. In some instances, the combination of a Btk inhibitor, an immunomodulating agent, and an additional anticancer agent sensitizes the cancer (e.g. solid tumors, hematologic cancers) to the additional anticancer agent, or to the combination of the Btk inhibitor, the immunomodulating agent, and the additional anticancer agent.

[00307] In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274),

Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the

immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TEVI3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the immunomodulating agent is an inhibitor of TIM3.

[00308] In some embodiments, the dose of ibrutinib is between about 10 mg to about 1000 mg. In some embodiments, the dose of Ibrutinib is about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 420 mg, about 450 mg, about 500 mg, about 550 mg, about 560 mg, about 600 mg, about 700 mg, about 800 mg, or about 840 mg. In some embodiments, the therapeutically-effective amount of ibrutinib is between about 40 mg and about 140 mg. In some embodiments, the therapeutically-effective amount of ibrutinib is between about 40 mg and about 100 mg. In some embodiments, the dose of ibrutinib is between about 40 mg and about 70 mg. In some embodiments, the dose of ibrutinib is about 40 mg. In some embodiments, ibrutinib is amorphous or crystalline. In some embodiments, ibrutinib is milled or a nano-particle. In some embodiments, the pharmaceutical composition is a combined dosage form.

[00309] Pharmaceutical combinations and/or compositions may be formulated in a conventional manner using one or more physiologically acceptable carriers including excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any of the well-known techniques, carriers, and excipients may be used as suitable and as understood in the art. A summary of pharmaceutical compositions described herein may be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa. : Mack Publishing Company, 1995);

Hoover, John E., Remington 's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N. Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkinsl999), herein incorporated by reference in their entirety. [00310] A pharmaceutical combination, as used herein, refers to a mixture of ibrutinib, an immunomodulating agent, and/or an additional therapeutic agent with other chemical components, such as carriers, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients.

[00311] In practicing the methods of treatment or use provided herein, therapeutically effective amounts of the compounds disclosed herein are administered having a disease, disorder, or condition to be treated. In some embodiments, the mammal is a human. The therapeutically effective amounts of the compounds may vary depending on the compounds, severity of the disease, the age and relative health of the subject, and other factors.

[00312] The term "combination" as used herein, means a product that results from the mixing or combining of ibrutinib and an immunomodulating agent (and any additional therapeutic agents) and includes both fixed and non-fixed combinations. The term "fixed combination" means that Ibrutinib and the immunomodulating agent are both administered in a single entity or dosage form. The term "non-fixed combination" means that ibrutinib and the immunomodulating agent are administered as separate entities or dosage forms either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides effective levels of the two compounds in the body of the patient. The latter also applies to cocktail therapy, e.g. the administration of three or more active ingredients.

[00313] In some embodiments, the pharmaceutical combination and/or composition described herein also include one or more pH adjusting agents or buffering agents, including acids such as acetic, boric, citric, lactic, phosphoric and hydrochloric acids; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris-hydroxymethylaminomethane; and buffers such as citrate/dextrose, sodium bicarbonate and ammonium chloride. Such acids, bases and buffers are included in an amount required to maintain pH of the composition in an acceptable range.

[00314] In some embodiments, the pharmaceutical combination and/or compositions also include one or more salts in an amount required to bring osmolality of the composition into an acceptable range. Such salts include those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium

thiosulfate, sodium bisulfite and ammonium sulfate.

[00315] The pharmaceutical formulations described herein can be administered to a subject by multiple administration routes, including but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal administration routes. The pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.

[00316] In some embodiments, pharmaceutical combination and/or compositions including a compound described herein are manufactured in a conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee- making, levigating, emulsifying, encapsulating, entrapping or compression processes.

[00317] "Antifoaming agents" reduce foaming during processing which can result in coagulation of aqueous dispersions, bubbles in the finished film, or generally impair processing. Exemplary anti-foaming agents include silicon emulsions or sorbitan sesquoleate.

[00318] "Antioxidants" include, for example, butylated hydroxytoluene (BHT), sodium ascorbate, ascorbic acid, sodium metabisulfite and tocopherol. In certain

embodiments, antioxidants enhance chemical stability where required.

[00319] In some embodiments, compositions provided herein also include one or more preservatives to inhibit microbial activity. Suitable preservatives include mercury-containing substances such as merfen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide and cetylpyridinium chloride.

[00320] In some embodiments, formulations described herein benefit from

antioxidants, metal chelating agents, thiol containing compounds and other general stabilizing agents. Examples of such stabilizing agents, include, but are not limited to: (a) about 0.5% to about 2% w/v glycerol, (b) about 0.1% to about 1% w/v methionine, (c) about 0.1% to about 2% w/v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% w/v ascorbic acid, (f) 0.003% to about 0.02% w/v polysorbate 80, (g) 0.001% to about 0.05% w/v. polysorbate 20, (h) arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrins, (1) pentosan polysulfate and other heparinoids, (m) divalent cations such as magnesium and zinc; or (n) combinations thereof.

[00321] "Binders" impart cohesive qualities and include, e.g., alginic acid and salts thereof; cellulose derivatives such as carboxymethylcellulose, methylcellulose (e.g.,

Methocel ^® ), hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel ), ethylcellulose (e.g., Ethocel ), and microcrystalline cellulose (e.g., Avicel ); microcrystalline dextrose; amylose; magnesium aluminum silicate; polysaccharide acids; bentonites; gelatin; polyvinylpyrrolidone/vinyl acetate copolymer; crospovidone; povidone; starch; pregelatinized starch; tragacanth, dextrin, a sugar, such as sucrose (e.g., Dipac ^® ), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (e.g., Xylitab ^® ), and lactose; a natural or synthetic gum such as acacia, tragacanth, ghatti gum, mucilage of isapol husks,

polyvinylpyrrolidone (e.g., Polyvidone ^® CL, Kollidon ^® CL, Polyplasdone ^® XL- 10), larch arabogalactan, Veegum ^® , polyethylene glycol, waxes, sodium alginate, and the like.

[00322] A "carrier" or "carrier materials" include any commonly used excipients in pharmaceutics and should be selected on the basis of compatibility with compounds disclosed herein, such as, compounds of ibrutinib, and the release profile properties of the desired dosage form. Exemplary carrier materials include, e.g., binders, suspending agents, disintegration agents, filling agents, surfactants, solubilizers, stabilizers, lubricants, wetting agents, diluents, and the like. "Pharmaceutically compatible carrier materials" include, but are not limited to, acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerine, magnesium silicate, polyvinylpyrrollidone (PVP), cholesterol, cholesterol esters, sodium caseinate, soy lecithin, taurocholic acid,

phosphotidylcholine, sodium chloride, tricalcium phosphate, dipotassium phosphate, cellulose and cellulose conjugates, sugars sodium stearoyl lactylate, carrageenan,

monoglyceride, diglyceride, pregelatinized starch, and the like. See, e.g., Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa. : Mack Publishing Company, 1995); Hoover, John E., Remington 's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N. Y., 1980; and Pharmaceutical Dosage Forms and Drug

Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkinsl999).

[00323] "Dispersing agents," and/or "viscosity modulating agents" include materials that control the diffusion and homogeneity of a drug through liquid media or a granulation method or blend method. In some embodiments, these agents also facilitate the effectiveness of a coating or eroding matrix. Exemplary diffusion facilitators/dispersing agents include, e.g., hydrophilic polymers, electrolytes, Tween ^® 60 or 80, PEG, polyvinylpyrrolidone (PVP;

commercially known as Plasdone ^® ), and the carbohydrate-based dispersing agents such as, for example, hydroxypropyl celluloses (e.g., HPC, HPC-SL, and HPC-L), hydroxypropyl methylcelluloses (e.g., HPMC K100, HPMC K4M, HPMC K15M, and HPMC K100M), carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate,

hydroxypropylmethylcellulose acetate stearate (HPMCAS), noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), vinyl

pyrrolidone/vinyl acetate copolymer (S630), 4-(l,l,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde (also known as tyloxapol), poloxamers (e.g., Pluronics F68 ^® , F88 ^® , and F108 ^® , which are block copolymers of ethylene oxide and propylene oxide); and poloxamines (e.g., Tetronic 908 ^® , also known as Poloxamine 908 ^® , which is a tetrafunctional block copolymer derived from sequential addition of propylene oxide and ethylene oxide to ethylenediamine (BASF Corporation, Parsippany, N.J.)),

polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, polyvinylpyrrolidone/vinyl acetate copolymer (S-630), polyethylene glycol, e.g., the polyethylene glycol can have a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 7000 to about 5400, sodium

carboxymethylcellulose, methylcellulose, polysorbate-80, sodium alginate, gums, such as, e.g., gum tragacanth and gum acacia, guar gum, xanthans, including xanthan gum, sugars, cellulosics, such as, e.g., sodium carboxymethylcellulose, methylcellulose, sodium

carboxymethylcellulose, polysorbate-80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone, carbomers, polyvinyl alcohol (PVA), alginates, chitosans and combinations thereof. Plasticizers such as cellulose or triethyl cellulose can also be used as dispersing agents. Dispersing agents particularly useful in liposomal dispersions and self-emulsifying dispersions are dimyristoyl phosphatidyl choline, natural phosphatidyl choline from eggs, natural phosphatidyl glycerol from eggs, cholesterol and isopropyl my ri state.

[00324] Combinations of one or more erosion facilitator with one or more diffusion facilitator can also be used in the present compositions.

[00325] The term "diluent" refers to chemical compounds that are used to dilute the compound of interest prior to delivery. Diluents can also be used to stabilize compounds because they can provide a more stable environment. Salts dissolved in buffered solutions (which also can provide pH control or maintenance) are utilized as diluents in the art, including, but not limited to a phosphate buffered saline solution. In certain embodiments, diluents increase bulk of the composition to facilitate compression or create sufficient bulk for homogenous blend for capsule filling. Such compounds include e.g., lactose, starch, mannitol, sorbitol, dextrose, microcrystalline cellulose such as Avicel ^® ; dibasic calcium phosphate, dicalcium phosphate dihydrate; tricalcium phosphate, calcium phosphate; anhydrous lactose, spray-dried lactose; pregelatinized starch, compressible sugar, such as Di- Pac ^® (Amstar); mannitol, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate stearate, sucrose-based diluents, confectioner's sugar; monobasic calcium sulfate monohydrate, calcium sulfate dihydrate; calcium lactate trihydrate, dextrates; hydrolyzed cereal solids, amylose; powdered cellulose, calcium carbonate; glycine, kaolin; mannitol, sodium chloride; inositol, bentonite, and the like.

[00326] The term "disintegrate" includes both the dissolution and dispersion of the dosage form when contacted with gastrointestinal fluid. "Disintegration agents or

disintegrants" facilitate the breakup or disintegration of a substance. Examples of

disintegration agents include a starch, e.g., a natural starch such as corn starch or potato starch, a pregelatinized starch such as National 1551 or Amijel ^® , or sodium starch glycolate such as Promogel ^® or Explotab ^® , a cellulose such as a wood product, methylcrystalline cellulose, e.g., Avicel ^® , Avicel ^® PH101, Avicel ^® PH102, Avicel ^® PH105, Elcema ^® P100, Emcocel ^® , Vivacel ^® , Ming Tia ^® , and Solka-Floc ^® , methylcellulose, croscarmellose, or a cross-linked cellulose, such as cross-linked sodium carboxymethylcellulose (Ac-Di-Sol ^® ), cross-linked carboxymethylcellulose, or cross-linked croscarmellose, a cross-linked starch such as sodium starch glycolate, a cross-linked polymer such as crospovidone, a cross-linked polyvinylpyrrolidone, alginate such as alginic acid or a salt of alginic acid such as sodium alginate, a clay such as Veegum ^® HV (magnesium aluminum silicate), a gum such as agar, guar, locust bean, Karaya, pectin, or tragacanth, sodium starch glycolate, bentonite, a natural sponge, a surfactant, a resin such as a cation-exchange resin, citrus pulp, sodium lauryl sulfate, sodium lauryl sulfate in combination starch, and the like.

[00327] "Drug absorption" or "absorption" typically refers to the process of movement of drug from site of administration of a drug across a barrier into a blood vessel or the site of action, e.g., a drug moving from the gastrointestinal tract into the portal vein or lymphatic system.

[00328] An "enteric coating" is a substance that remains substantially intact in the stomach but dissolves and releases the drug in the small intestine or colon. Generally, the enteric coating comprises a polymeric material that prevents release in the low pH

environment of the stomach but that ionizes at a higher pH, typically a pH of 6 to 7, and thus dissolves sufficiently in the small intestine or colon to release the active agent therein.

[00329] "Erosion facilitators" include materials that control the erosion of a particular material in gastrointestinal fluid. Erosion facilitators are generally known to those of ordinary skill in the art. Exemplary erosion facilitators include, e.g., hydrophilic polymers, electrolytes, proteins, peptides, and amino acids.

[00330] "Filling agents" include compounds such as lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrates, dextran, starches, pregelatinized starch, sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.

[00331] "Flavoring agents" and/or "sweeteners" useful in the formulations described herein, include, e.g., acacia syrup, acesulfame K, alitame, anise, apple, aspartame, banana, Bavarian cream, berry, black currant, butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream, cotton candy, cocoa, cola, cool cherry, cool citrus, cyclamate, cylamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhetinate, glycyrrhiza (licorice) syrup, grape, grapefruit, honey, isomalt, lemon, lime, lemon cream, monoammonium glyrrhizinate

(MagnaSweet ^® ), maltol, mannitol, maple, marshmallow, menthol, mint cream, mixed berry, neohesperidine DC, neotame, orange, pear, peach, peppermint, peppermint cream, Prosweet ^® Powder, raspberry, root beer, rum, saccharin, safrole, sorbitol, spearmint, spearmint cream, strawberry, strawberry cream, stevia, sucralose, sucrose, sodium saccharin, saccharin, aspartame, acesulfame potassium, mannitol, talin, sylitol, sucralose, sorbitol, Swiss cream, tagatose, tangerine, thaumatin, tutti fruitti, vanilla, walnut, watermelon, wild cherry, wintergreen, xylitol, or any combination of these flavoring ingredients, e.g., anise-menthol, cherry-anise, cinnamon-orange, cherry-cinnamon, chocolate-mint, honey-lemon, lemon-lime, lemon-mint, menthol-eucalyptus, orange-cream, vanilla-mint, and mixtures thereof.

[00332] "Lubricants" and "glidants" are compounds that prevent, reduce or inhibit adhesion or friction of materials. Exemplary lubricants include, e.g., stearic acid, calcium hydroxide, talc, sodium stearyl fumerate, a hydrocarbon such as mineral oil, or hydrogenated vegetable oil such as hydrogenated soybean oil (Sterotex ^® ), higher fatty acids and their alkali- metal and alkaline earth metal salts, such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearates, glycerol, talc, waxes, Stearowet ^® , boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, a polyethylene glycol (e.g., PEG-4000) or a methoxypolyethylene glycol such as Carbowax™, sodium oleate, sodium benzoate, glyceryl behenate, polyethylene glycol, magnesium or sodium lauryl sulfate, colloidal silica such as Syloid™, Cab-O-Sil ^® , a starch such as corn starch, silicone oil, a surfactant, and the like.

[00333] A "measurable serum concentration" or "measurable plasma concentration" describes the blood serum or blood plasma concentration, typically measured in mg, μg, or ng of therapeutic agent per mL, dL, or L of blood serum, absorbed into the bloodstream after administration. As used herein, measurable plasma concentrations are typically measured in ng/ml or μg/ml.

[00334] "Pharmacodynamics" refers to the factors which determine the biologic response observed relative to the concentration of drug at a site of action.

[00335] "Pharmacokinetics" refers to the factors which determine the attainment and maintenance of the appropriate concentration of drug at a site of action.

[00336] "Plasticizers" are compounds used to soften the microencapsulation material or film coatings to make them less brittle. Suitable plasticizers include, e.g., polyethylene glycols such as PEG 300, PEG 400, PEG 600, PEG 1450, PEG 3350, and PEG 800, stearic acid, propylene glycol, oleic acid, triethyl cellulose and triacetin. In some embodiments, plasticizers can also function as dispersing agents or wetting agents.

[00337] "Solubilizers" include compounds such as triacetin, triethylcitrate, ethyl oleate, ethyl caprylate, sodium lauryl sulfate, sodium doccusate, vitamin E TPGS,

dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropylmethyl cellulose, hydroxypropyl cyclodextrins, ethanol, n-butanol, isopropyl alcohol, cholesterol, bile salts, polyethylene glycol 200-600, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide and the like.

[00338] "Stabilizers" include compounds such as any anti oxidation agents, buffers, acids, preservatives and the like.

[00339] "Steady state," as used herein, is when the amount of drug administered is equal to the amount of drug eliminated within one dosing interval resulting in a plateau or constant plasma drug exposure.

[00340] "Suspending agents" include compounds such as polyvinylpyrrolidone, e.g., polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, vinyl pyrrolidone/vinyl acetate copolymer (S630), polyethylene glycol, e.g., the polyethylene glycol can have a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 7000 to about 5400, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, hydroxymethylcellulose acetate stearate, polysorbate-80, hydroxy ethylcellulose, sodium alginate, gums, such as, e.g., gum tragacanth and gum acacia, guar gum, xanthans, including xanthan gum, sugars, cellulosics, such as, e.g., sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose,

hydroxypropylmethylcellulose, hydroxyethylcellulose, polysorbate-80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone and the like.

[00341] "Surfactants" include compounds such as sodium lauryl sulfate, sodium docusate, Tween 60 or 80, triacetin, vitamin E TPGS, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, polaxomers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, e.g., Pluronic ^® (BASF), and the like. Some other surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, e.g.,

polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol 10, octoxynol 40. In some embodiments, surfactants are included to enhance physical stability or for other purposes.

[00342] "Viscosity enhancing agents" include, e.g., methyl cellulose, xanthan gum, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose acetate stearate, hydroxypropylmethyl cellulose phthalate, carbomer, polyvinyl alcohol, alginates, acacia, chitosans and combinations thereof.

[00343] "Wetting agents" include compounds such as oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, sodium docusate, sodium oleate, sodium lauryl sulfate, sodium doccusate, triacetin, Tween 80, vitamin E TPGS, ammonium salts and the like.

Dosage Forms

[00344] Disclosed herein, in certain embodiments, are dosage forms which comprise a

Btk inhibitor and an immunomodulating agent. In some embodiments, the Btk inhibitor is ibrutinib. In some embodiments, the dosage form is a combined dosage form. In some embodiments, the dosage form is a solid oral dosage form. In some embodiments, the dosage form is a tablet, pill, or capsule. In some embodiments, the dosage form is a controlled release dosage form, delayed release dosage form, extended release dosage form, pulsatile release dosage form, multiparticulate dosage form, or mixed immediate release and controlled release formulation. In some embodiments, the dosage form comprises a controlled release coating. In some embodiments, the dosage forms comprises a first controlled release coating which controls the release of Ibrutinib and a second controlled release coating which controls the release of the immunomodulating agent. In some embodiments, the combination provides a synergistic or additive therapeutic effect compared to administration of ibrutinib or the second anticancer agent alone. [00345] In some embodiments, the immunomodulating agent is an antibody that binds specifically to Programmed Death-Ligand 1 (PD-L1, also known as B7-H1, CD274), Programmed Death 1 (PD-1), CTLA-4, PD-L2 (B7-DC, CD273), LAG3, TIM3, TIM4, 2B4, A2aR, B7-H2, B7-H3, B7-H4, B7-H6, BTLA, CD2, CD27, CD28, CD30, CD30L, CD40, CD40L, CD48, CD58, CD70, CD80, CD86, CD96, CD112, CD113, CD137, CD137L, CD155, CD160, CD226, CD276, CRTAM, DR3, GAL9, GITR, GITRL, HAVCR2, HVEM, IDOl, ID02, ICOS (inducible T cell costimulator), ICOSL, ILT3, ILT4, KIR, LAIR1, LIGHT, LTBR, MARCO (macrophage receptor with collageneous structure), MHC class I, MHC class II, KG2A, PS (phosphatidylserine), OX-40, OX40L, SLAM, TD02, TIGHT, TL1A, VISTA, VTCN1, or any combinations thereof. In some embodiments, the

immunomodulating agent is an inhibitor of IDOl, ID02, TD02, A2aR, PD-L1, PD-1, CTLA-4, LAG3, or TIM3. In some embodiments, the immunomodulating agent is an inhibitor of PD-L1. In some embodiments, the immunomodulating agent is an inhibitor of PD-1. In some embodiments, the immunomodulating agent is an inhibitor of CTLA-4. In some embodiments, the inhibitor of CTLA-4 is ipilimumab. In some embodiments, the immunomodulating agent is an inhibitor of LAG3. In some embodiments, the

immunomodulating agent is an inhibitor of TIM3. In some embodiments, the Btk inhibitor is ibrutinib and the inhibitor of CTLA-4 is ipilimumab.

[00346] In some embodiments, the dose of ibrutinib is between about 10 mg to about 1000 mg. In some embodiments, the dose of ibrutinib is about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 420 mg, about 450 mg, about 500 mg, about 560 mg, about 550 mg, about 600 mg, about 700 mg, about 800 mg, or about 840 mg. In some embodiments, the therapeutically-effective amount of ibrutinib is between about 40 mg and about 140 mg. In some embodiments, the therapeutically-effective amount of ibrutinib is between about 40 mg and about 100 mg. In some embodiments, the dose of ibrutinib is between about 40 mg and about 70 mg. In some embodiments, the dose of ibrutinib is about 40 mg. In some embodiments, ibrutinib is amorphous or crystalline. [00347] The pharmaceutical combination described herein may be formulated for administration via any conventional means including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, or intramuscular), buccal, intranasal, rectal or transdermal administration routes. As used herein, the terms "subject", "individual" and "patient" are used interchangeably and mean an animal, preferably a mammal, including a human or non- human. None of the terms require the supervision (continuous or otherwise) of a medical professional.

[00348] The pharmaceutical combination described herein are formulated into any suitable dosage form, including but not limited to, solid oral dosage forms, controlled release formulations, fast melt formulations, effervescent formulations, tablets, powders, pills, capsules, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate release and controlled release formulations.

[00349] Pharmaceutical preparations for oral use can be obtained by mixing one or more solid excipient with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose,

hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as:

polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. In some embodiments, disintegrating agents are added, such as the cross-linked croscarmellose sodium,

polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

[00350] Dragee cores are provided with suitable coatings. For this purpose, in some embodiments, concentrated sugar solutions are used, which, in particular embodiments, optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. In some embodiments, dyestuffs or pigments are added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

[00351] Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In some embodiments, in soft capsules, the active compounds are dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, in some embodiments, stabilizers are added. All formulations for oral administration should be in dosages suitable for such administration.

[00352] In some embodiments, the solid dosage forms disclosed herein are in the form of a tablet, (including a suspension tablet, a fast-melt tablet, a bite-disintegration tablet, a rapid-disintegration tablet, an effervescent tablet, or a caplet), a pill, a powder (including a sterile packaged powder, a dispensable powder, or an effervescent powder) a capsule (including both soft or hard capsules, e.g., capsules made from animal-derived gelatin or plant-derived HPMC, or "sprinkle capsules"), solid dispersion, solid solution, bioerodible dosage form, controlled release formulations, pulsatile release dosage forms, multiparticulate dosage forms, pellets, granules, or an aerosol. In other embodiments, the pharmaceutical formulation is in the form of a powder. In still other embodiments, the pharmaceutical formulation is in the form of a tablet, including but not limited to, a fast-melt tablet.

Additionally, in some embodiments, pharmaceutical formulations described herein are administered as a single capsule or in multiple capsule dosage form. In some embodiments, the pharmaceutical formulation is administered in two, or three, or four, capsules or tablets.

[00353] In some embodiments, solid dosage forms, e.g., tablets, effervescent tablets, and capsules, are prepared by mixing particles of ibrutinib, with one or more pharmaceutical excipients to form a bulk blend composition. When referring to these bulk blend

compositions as homogeneous, it is meant that the particles of ibrutinib are dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms, such as tablets, pills, and capsules. In some embodiments, the individual unit dosages also include film coatings, which disintegrate upon oral ingestion or upon contact with diluent. These formulations can be manufactured by conventional pharmacological techniques.

[00354] Conventional pharmacological techniques include, e.g., one or a combination of methods: (1) dry mixing, (2) direct compression, (3) milling, (4) dry or non-aqueous granulation, (5) wet granulation, or (6) fusion. See, e.g., Lachman et al., The Theory and Practice of Industrial Pharmacy (1986). Other methods include, e.g., spray drying, pan coating, melt granulation, granulation, fluidized bed spray drying or coating (e.g., wurster coating), tangential coating, top spraying, tableting, extruding and the like. [00355] The pharmaceutical solid dosage forms described herein can include a compound described herein and one or more pharmaceutically acceptable additives such as a compatible carrier, binder, filling agent, suspending agent, flavoring agent, sweetening agent, disintegrating agent, dispersing agent, surfactant, lubricant, colorant, diluent, solubilizer, moistening agent, plasticizer, stabilizer, penetration enhancer, wetting agent, anti-foaming agent, antioxidant, preservative, or one or more combination thereof. In still other aspects, using standard coating procedures, such as those described in Remington 's Pharmaceutical Sciences, 20th Edition (2000), a film coating is provided around the formulation of ibrutinib. In another embodiment, some or all of the particles of ibrutinib, are not microencapsulated and are uncoated.

[00356] Suitable carriers for use in the solid dosage forms described herein include, but are not limited to, acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate, calcium lactate, maltodextrin, glycerine, magnesium silicate, sodium caseinate, soy lecithin, sodium chloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyl lactylate, carrageenan, monoglyceride, diglyceride, pregelatinized starch,

hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate stearate, sucrose, microcrystalline cellulose, lactose, mannitol and the like.

[00357] Suitable filling agents for use in the solid dosage forms described herein include, but are not limited to, lactose, calcium carbonate, calcium phosphate, dibasic calcium phosphate, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrates, dextran, starches, pregelatinized starch, hydroxypropylmethycellulose (HPMC), hydroxypropylmethycellulose phthalate, hydroxypropylmethylcellulose acetate stearate (HPMCAS), sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.

[00358] In order to release the compound of one or more of the therapeutic agents described herein, from a solid dosage form matrix as efficiently as possible, disintegrants are often used in the formulation, especially when the dosage forms are compressed with binder. Disintegrants help rupturing the dosage form matrix by swelling or capillary action when moisture is absorbed into the dosage form. Suitable disintegrants for use in the solid dosage forms described herein include, but are not limited to, natural starch such as corn starch or potato starch, a pregelatinized starch such as National 1551 or Amijel ^® , or sodium starch glycolate such as Promogel ^® or Explotab ^® , a cellulose such as a wood product,

methylcrystalline cellulose, e.g., Avicel ^® , Avicel ^® PH101, Avicel ^® PH102, Avicel ^® PH105, Elcema ^® PI 00, Emcocel ^® , Vivacel ^® , Ming Tia ^® , and Solka-Floc ^® , methylcellulose, croscarmellose, or a cross-linked cellulose, such as cross-linked sodium

carboxymethylcellulose (Ac-Di-Sol ^® ), cross-linked carboxymethylcellulose, or cross-linked croscarmellose, a cross-linked starch such as sodium starch glycolate, a cross-linked polymer such as crospovidone, a cross-linked polyvinylpyrrolidone, alginate such as alginic acid or a salt of alginic acid such as sodium alginate, a clay such as Veegum ^® HV (magnesium aluminum silicate), a gum such as agar, guar, locust bean, Karaya, pectin, or tragacanth, sodium starch glycolate, bentonite, a natural sponge, a surfactant, a resin such as a cation- exchange resin, citrus pulp, sodium lauryl sulfate, sodium lauryl sulfate in combination starch, and the like.

[00359] Binders impart cohesiveness to solid oral dosage form formulations: for powder filled capsule formulation, they aid in plug formation that can be filled into soft or hard shell capsules and for tablet formulation, they ensure the tablet remaining intact after compression and help assure blend uniformity prior to a compression or fill step. Materials suitable for use as binders in the solid dosage forms described herein include, but are not limited to, carboxymethylcellulose, methylcellulose (e.g., Methocel ^® ),

hydroxypropylmethylcellulose (e.g. Hypromellose USP Pharmacoat-603,

hydroxypropylmethylcellulose acetate stearate (Aqoate HS-LF and HS),

hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel ^® ), ethylcellulose (e.g., Ethocel ^® ), and microcrystalline cellulose (e.g., Avicel ^® ), microcrystalline dextrose, amylose, magnesium aluminum silicate, polysaccharide acids, bentonites, gelatin, polyvinylpyrrolidone/vinyl acetate copolymer, crospovidone, povidone, starch, pregelatinized starch, tragacanth, dextrin, a sugar, such as sucrose (e.g., Dipac ^® ), glucose, dextrose, molasses, mannitol, sorbitol, xylitol (e.g., Xylitab ^® ), lactose, a natural or synthetic gum such as acacia, tragacanth, ghatti gum, mucilage of isapol husks, starch, polyvinylpyrrolidone (e.g., Povidone ^® CL, Kollidon ^® CL, Polyplasdone ^® XL- 10, and Povidone ^® K-12), larch arabogalactan, Veegum ^® , polyethylene glycol, waxes, sodium alginate, and the like.

[00360] In general, binder levels of 20-70% are used in powder-filled gelatin capsule formulations. Binder usage level in tablet formulations varies whether direct compression, wet granulation, roller compaction, or usage of other excipients such as fillers which itself can act as moderate binder. Formulators skilled in art can determine the binder level for the formulations, but binder usage level of up to 70% in tablet formulations is common.

[00361] Suitable lubricants or glidants for use in the solid dosage forms described herein include, but are not limited to, stearic acid, calcium hydroxide, talc, corn starch, sodium stearyl fumerate, alkali-metal and alkaline earth metal salts, such as aluminum, calcium, magnesium, zinc, stearic acid, sodium stearates, magnesium stearate, zinc stearate, waxes, Stearowet ^® , boric acid, sodium benzoate, sodium acetate, sodium chloride, leucine, a polyethylene glycol or a methoxypolyethylene glycol such as Carbowax™, PEG 4000, PEG 5000, PEG 6000, propylene glycol, sodium oleate, glyceryl behenate, glyceryl

palmitostearate, glyceryl benzoate, magnesium or sodium lauryl sulfate, and the like.

[00362] Suitable diluents for use in the solid dosage forms described herein include, but are not limited to, sugars (including lactose, sucrose, and dextrose), polysaccharides (including dextrates and maltodextrin), polyols (including mannitol, xylitol, and sorbitol), cyclodextrins and the like.

[00363] The term "non water-soluble diluent" represents compounds typically used in the formulation of pharmaceuticals, such as calcium phosphate, calcium sulfate, starches, modified starches and microcrystalline cellulose, and microcellulose (e.g., having a density of about 0.45 g/cm ³ , e.g. Avicel, powdered cellulose), and talc.

[00364] Suitable wetting agents for use in the solid dosage forms described herein include, for example, oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, quaternary ammonium compounds (e.g., Polyquat 10 ^® ), sodium oleate, sodium lauryl sulfate, magnesium stearate, sodium docusate, triacetin, vitamin E TPGS and the like.

[00365] Suitable surfactants for use in the solid dosage forms described herein include, for example, sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan

monooleate, polysorbates, polaxomers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, e.g., Pluronic ^® (BASF), and the like.

[00366] Suitable suspending agents for use in the solid dosage forms described here include, but are not limited to, polyvinylpyrrolidone, e.g., polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, polyethylene glycol, e.g., the polyethylene glycol can have a molecular weight of about 300 to about 6000, or about 3350 to about 4000, or about 7000 to about 5400, vinyl

pyrrolidone/vinyl acetate copolymer (S630), sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, polysorbate-80, hydroxyethylcellulose, sodium alginate, gums, such as, e.g., gum tragacanth and gum acacia, guar gum, xanthans, including xanthan gum, sugars, cellulosics, such as, e.g., sodium carboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, polysorbate-80, sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan monolaurate, povidone and the like.

[00367] Suitable antioxidants for use in the solid dosage forms described herein include, for example, e.g., butylated hydroxytoluene (BHT), sodium ascorbate, and

tocopherol.

[00368] It should be appreciated that there is considerable overlap between additives used in the solid dosage forms described herein. Thus, the above-listed additives should be taken as merely exemplary, and not limiting, of the types of additives that can be included in solid dosage forms described herein. The amounts of such additives can be readily

determined by one skilled in the art, according to the particular properties desired.

[00369] In other embodiments, one or more layers of the pharmaceutical formulation are plasticized. Illustratively, a plasticizer is generally a high boiling point solid or liquid. Suitable plasticizers can be added from about 0.01% to about 50% by weight (w/w) of the coating composition. Plasticizers include, but are not limited to, diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearate, and castor oil.

[00370] Compressed tablets are solid dosage forms prepared by compacting the bulk blend of the formulations described above. In various embodiments, compressed tablets which are designed to dissolve in the mouth will include one or more flavoring agents. In other embodiments, the compressed tablets will include a film surrounding the final compressed tablet. In some embodiments, the film coating can provide a delayed release of ibrutinib or the second agent, from the formulation. In other embodiments, the film coating aids in patient compliance (e.g., Opadry ^® coatings or sugar coating). Film coatings including Opadry ^® typically range from about 1% to about 3% of the tablet weight. In other

embodiments, the compressed tablets include one or more excipients.

[00371] In some embodiments, a capsule is prepared, for example, by placing the bulk blend of the formulation of ibrutinib or the second agent, described above, inside of a capsule. In some embodiments, the formulations (non-aqueous suspensions and solutions) are placed in a soft gelatin capsule. In other embodiments, the formulations are placed in standard gelatin capsules or non-gelatin capsules such as capsules comprising HPMC. In other embodiments, the formulation is placed in a sprinkle capsule, wherein the capsule can be swallowed whole or the capsule can be opened and the contents sprinkled on food prior to eating. In some embodiments, the therapeutic dose is split into multiple (e.g., two, three, or four) capsules. In some embodiments, the entire dose of the formulation is delivered in a capsule form.

[00372] In various embodiments, the particles of ibrutinib, and one or more excipients are dry blended and compressed into a mass, such as a tablet, having a hardness sufficient to provide a pharmaceutical composition that substantially disintegrates within less than about 30 minutes, less than about 35 minutes, less than about 40 minutes, less than about 45 minutes, less than about 50 minutes, less than about 55 minutes, or less than about 60 minutes, after oral administration, thereby releasing the formulation into the gastrointestinal fluid.

[00373] In another aspect, in some embodiments, dosage forms include

microencapsulated formulations. In some embodiments, one or more other compatible materials are present in the microencapsulation material. Exemplary materials include, but are not limited to, pH modifiers, erosion facilitators, anti-foaming agents, antioxidants, flavoring agents, and carrier materials such as binders, suspending agents, disintegration agents, filling agents, surfactants, solubilizers, stabilizers, lubricants, wetting agents, and diluents.

[00374] Materials useful for the microencapsulation described herein include materials compatible with ibrutinib, which sufficiently isolate the compound of any of ibrutinib, from other non-compatible excipients. Materials compatible with compounds of any of ibrutinib, are those that delay the release of the compounds of any of ibrutinib, in vivo.

[00375] Exemplary microencapsulation materials useful for delaying the release of the formulations including compounds described herein, include, but are not limited to, hydroxypropyl cellulose ethers (HPC) such as Klucel ^® or Nisso HPC, low- substituted hydroxypropyl cellulose ethers (L-HPC), hydroxypropyl methyl cellulose ethers (HPMC) such as Seppifilm-LC, Pharmacoat ^® , Metolose SR, Methocel ^® -E, Opadry YS, PrimaFlo, Benecel MP824, and Benecel MP843, methylcellulose polymers such as Methocel ^® -A, hydroxypropylmethylcellulose acetate stearate Aqoat (HF-LS, HF-LG,HF-MS) and

Metolose ^® , Ethylcelluloses (EC) and mixtures thereof such as E461, Ethocel ^® , Aqualon ^® -EC, Surelease ^® , Polyvinyl alcohol (PVA) such as Opadry AMB, hydroxyethylcelluloses such as Natrosol ^® , carboxymethylcelluloses and salts of carboxymethylcelluloses (CMC) such as Aqualon ^® -CMC, polyvinyl alcohol and polyethylene glycol co-polymers such as Kollicoat IR ^® , monoglycerides (Myverol), triglycerides (KLX), polyethylene glycols, modified food starch, acrylic polymers and mixtures of acrylic polymers with cellulose ethers such as Eudragit ^® EPO, Eudragit ^® L30D-55, Eudragit ^® FS 30D Eudragit ^® L100-55, Eudragit ^® LlOO, Eudragit ^® S100, Eudragit ^® RD100, Eudragit ^® E100, Eudragit ^® L12.5, Eudragit ^® S12.5, Eudragit NE30D, and Eudragit NE 40D, cellulose acetate phthalate, sepifilms such as mixtures of HPMC and stearic acid, cyclodextrins, and mixtures of these materials.

[00376] In still other embodiments, plasticizers such as polyethylene glycols, e.g., PEG

300, PEG 400, PEG 600, PEG 1450, PEG 3350, and PEG 800, stearic acid, propylene glycol, oleic acid, and triacetin are incorporated into the microencapsulation material. In other embodiments, the microencapsulating material useful for delaying the release of the pharmaceutical compositions is from the USP or the National Formulary (NF). In yet other embodiments, the microencapsulation material is Klucel. In still other embodiments, the microencapsulation material is methocel.

[00377] In some embodiments, microencapsulated compounds of any of ibrutinib, are formulated by methods known by one of ordinary skill in the art. Such known methods include, e.g., spray drying processes, spinning disk-solvent processes, hot melt processes, spray chilling methods, fluidized bed, electrostatic deposition, centrifugal extrusion, rotational suspension separation, polymerization at liquid-gas or solid-gas interface, pressure extrusion, or spraying solvent extraction bath. In addition to these, several chemical techniques, e.g., complex coacervation, solvent evaporation, polymer-polymer

incompatibility, interfacial polymerization in liquid media, in situ polymerization, in-liquid drying, and desolvation in liquid media could also be used. Furthermore, in some

embodiments, other methods such as roller compaction, extrusion/spheronization, coacervation, or nanoparticle coating are used.

[00378] In one embodiment, the particles of compounds of any of ibrutinib, are microencapsulated prior to being formulated into one of the above forms. In still another embodiment, some or most of the particles are coated prior to being further formulated by using standard coating procedures, such as those described in Remington 's Pharmaceutical Sciences, 20th Edition (2000).

[00379] In other embodiments, the solid dosage formulations of the compounds of any of ibrutinib, are plasticized (coated) with one or more layers. Illustratively, a plasticizer is generally a high boiling point solid or liquid. Suitable plasticizers can be added from about 0.01% to about 50%) by weight (w/w) of the coating composition. Plasticizers include, but are not limited to, diethyl phthalate, citrate esters, polyethylene glycol, glycerol, acetylated glycerides, triacetin, polypropylene glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearate, and castor oil.

[00380] In other embodiments, a powder including the formulations with a compound of any of ibrutinib, described herein, is formulated to include one or more pharmaceutical excipients and flavors. In some embodiments, such a powder is prepared, for example, by mixing the formulation and optional pharmaceutical excipients to form a bulk blend composition. Additional embodiments also include a suspending agent and/or a wetting agent. This bulk blend is uniformly subdivided into unit dosage packaging or multi-dosage packaging units.

[00381] In still other embodiments, effervescent powders are also prepared in accordance with the present disclosure. Effervescent salts have been used to disperse medicines in water for oral administration. Effervescent salts are granules or coarse powders containing a medicinal agent in a dry mixture, usually composed of sodium bicarbonate, citric acid and/or tartaric acid. When salts of the compositions described herein are added to water, the acids and the base react to liberate carbon dioxide gas, thereby causing

"effervescence." Examples of effervescent salts include, e.g., the following ingredients:

sodium bicarbonate or a mixture of sodium bicarbonate and sodium carbonate, citric acid and/or tartaric acid. Any acid-base combination that results in the liberation of carbon dioxide can be used in place of the combination of sodium bicarbonate and citric and tartaric acids, as long as the ingredients were suitable for pharmaceutical use and result in a pH of about 6.0 or higher.

[00382] In some embodiments, the solid dosage forms described herein can be formulated as enteric coated delayed release oral dosage forms, i.e., as an oral dosage form of a pharmaceutical composition as described herein which utilizes an enteric coating to affect release in the small intestine of the gastrointestinal tract. In some embodiments, the enteric coated dosage form is a compressed or molded or extruded tablet/mold (coated or uncoated) containing granules, powder, pellets, beads or particles of the active ingredient and/or other composition components, which are themselves coated or uncoated. In some embodiments, the enteric coated oral dosage form is a capsule (coated or uncoated) containing pellets, beads or granules of the solid carrier or the composition, which are themselves coated or uncoated.

[00383] The term "delayed release" as used herein refers to the delivery so that the release can be accomplished at some generally predictable location in the intestinal tract more distal to that which would have been accomplished if there had been no delayed release alterations. In some embodiments the method for delay of release is coating. Any coatings should be applied to a sufficient thickness such that the entire coating does not dissolve in the gastrointestinal fluids at pH below about 5, but does dissolve at pH about 5 and above. It is expected that any anionic polymer exhibiting a pH-dependent solubility profile can be used as an enteric coating in the methods and compositions described herein to achieve delivery to the lower gastrointestinal tract. In some embodiments the polymers described herein are anionic carboxylic polymers. In other embodiments, the polymers and compatible mixtures thereof, and some of their properties, include, but are not limited to:

[00384] Shellac, also called purified lac, a refined product obtained from the resinous secretion of an insect. This coating dissolves in media of pH >7;

[00385] Acrylic polymers. The performance of acrylic polymers (primarily their solubility in biological fluids) can vary based on the degree and type of substitution.

Examples of suitable acrylic polymers include methacrylic acid copolymers and ammonium methacrylate copolymers. The Eudragit series E, L, S, RL, RS and E (Rohm Pharma) are available as solubilized in organic solvent, aqueous dispersion, or dry powders. The Eudragit series RL, NE, and RS are insoluble in the gastrointestinal tract but are permeable and are used primarily for colonic targeting. The Eudragit series E dissolve in the stomach. The Eudragit series L, L-30D and S are insoluble in stomach and dissolve in the intestine;

[00386] Cellulose Derivatives. Examples of suitable cellulose derivatives are: ethyl cellulose; reaction mixtures of partial acetate esters of cellulose with phthalic anhydride. The performance can vary based on the degree and type of substitution. Cellulose acetate phthalate (CAP) dissolves in pH >6. Aquateric (FMC) is an aqueous based system and is a spray dried CAP psuedolatex with particles <1 μπι. Other components in Aquateric can include pluronics, Tweens, and acetylated monoglycerides. Other suitable cellulose derivatives include: cellulose acetate trimellitate (Eastman); methylcellulose (Pharmacoat, Methocel); hydroxypropylmethyl cellulose phthalate (HPMCP); hydroxypropylmethyl cellulose succinate (HPMCS); and hydroxypropylmethylcellulose acetate succinate (e.g., AQOAT (Shin Etsu)). The performance can vary based on the degree and type of substitution. For example, HPMCP such as, HP-50, HP-55, HP-55S, HP-55F grades are suitable. The performance can vary based on the degree and type of substitution. For example, suitable grades of hydroxypropylmethylcellulose acetate succinate include, but are not limited to, AS- LG (LF), which dissolves at pH 5, AS-MG (MF), which dissolves at pH 5.5, and AS-HG (HF), which dissolves at higher pH. These polymers are offered as granules, or as fine powders for aqueous dispersions; Poly Vinyl Acetate Phthalate (PVAP). PVAP dissolves in pH >5, and it is much less permeable to water vapor and gastric fluids.

[00387] In some embodiments, the coating can, and usually does, contain a plasticizer and possibly other coating excipients such as colorants, talc, and/or magnesium stearate, which are well known in the art. Suitable plasticizers include triethyl citrate (Citroflex 2), triacetin (glyceryl triacetate), acetyl triethyl citrate (Citroflec A2), Carbowax 400 (polyethylene glycol 400), diethyl phthalate, tributyl citrate, acetylated monoglycerides, glycerol, fatty acid esters, propylene glycol, and dibutyl phthalate. In particular, anionic carboxylic acrylic polymers usually will contain 10-25% by weight of a plasticizer, especially dibutyl phthalate, polyethylene glycol, triethyl citrate and triacetin. Conventional coating techniques such as spray or pan coating are employed to apply coatings. The coating thickness must be sufficient to ensure that the oral dosage form remains intact until the desired site of topical delivery in the intestinal tract is reached.

[00388] In some embodiments, colorants, detackifiers, surfactants, antifoaming agents, lubricants (e.g., carnuba wax or PEG) are added to the coatings besides plasticizers to solubilize or disperse the coating material, and to improve coating performance and the coated product.

[00389] In other embodiments, the formulations described herein, which include ibrutinib, are delivered using a pulsatile dosage form. A pulsatile dosage form is capable of providing one or more immediate release pulses at predetermined time points after a controlled lag time or at specific sites. Many other types of controlled release systems known to those of ordinary skill in the art and are suitable for use with the formulations described herein. Examples of such delivery systems include, e.g., polymer-based systems, such as polylactic and polyglycolic acid, plyanhydrides and polycaprolactone; porous matrices, nonpolymer-based systems that are lipids, including sterols, such as cholesterol, cholesterol esters and fatty acids, or neutral fats, such as mono-, di- and triglycerides; hydrogel release systems; silastic systems; peptide-based systems; wax coatings, bioerodible dosage forms, compressed tablets using conventional binders and the like. See, e.g., Liberman et al., Pharmaceutical Dosage Forms, 2 Ed., Vol. 1, pp. 209-214 (1990); Singh et al., Encyclopedia of Pharmaceutical Technology, 2 ^nd Ed., pp. 751-753 (2002); U.S. Pat. Nos. 4,327,725, 4,624,848, 4,968,509, 5,461,140, 5,456,923, 5,516,527, 5,622,721, 5,686,105, 5,700,410, 5,977,175, 6,465,014 and 6,932,983.

[00390] In some embodiments, pharmaceutical formulations are provided that include particles of ibrutinib, described herein and at least one dispersing agent or suspending agent for oral administration to a subject. In some embodiments, the formulations are a powder and/or granules for suspension, and upon admixture with water, a substantially uniform suspension is obtained.

[00391] Liquid formulation dosage forms for oral administration can be aqueous suspensions selected from the group including, but not limited to, pharmaceutically acceptable aqueous oral dispersions, emulsions, solutions, elixirs, gels, and syrups. See, e.g., Singh et al., Encyclopedia of Pharmaceutical Technology, 2 Ed., pp. 754-757 (2002). In addition, in some embodiments, the liquid dosage forms include additives, such as: (a) disintegrating agents; (b) dispersing agents; (c) wetting agents; (d) at least one preservative, (e) viscosity enhancing agents, (f) at least one sweetening agent, and (g) at least one flavoring agent. In some embodiments, the aqueous dispersions can further include a crystalline inhibitor.

[00392] The aqueous suspensions and dispersions described herein can remain in a homogenous state, as defined in The USP Pharmacists' Pharmacopeia (2005 edition, chapter 905), for at least 4 hours. The homogeneity should be determined by a sampling method consistent with regard to determining homogeneity of the entire composition. In one embodiment, an aqueous suspension can be re-suspended into a homogenous suspension by physical agitation lasting less than 1 minute. In another embodiment, an aqueous suspension can be re-suspended into a homogenous suspension by physical agitation lasting less than 45 seconds. In yet another embodiment, an aqueous suspension can be re-suspended into a homogenous suspension by physical agitation lasting less than 30 seconds. In still another embodiment, no agitation is necessary to maintain a homogeneous aqueous dispersion.

[00393] Examples of disintegrating agents for use in the aqueous suspensions and dispersions include, but are not limited to, a starch, e.g., a natural starch such as corn starch or potato starch, a pregelatinized starch such as National 1551 or Amijel ^® , or sodium starch glycolate such as Promogel ^® or Explotab ^® ; a cellulose such as a wood product,

methylcrystalline cellulose, e.g., Avicel ^® , Avicel ^® PH101, Avicel ^® PH102, Avicel ^® PH105, Elcema ^® PI 00, Emcocel ^® , Vivacel ^® , Ming Tia ^® , and Solka-Floc ^® , methylcellulose, croscarmellose, or a cross-linked cellulose, such as cross-linked sodium

carboxymethylcellulose (Ac-Di-Sol ^® ), cross-linked carboxymethylcellulose, or cross-linked croscarmellose; a cross-linked starch such as sodium starch glycolate; a cross-linked polymer such as crospovidone; a cross-linked polyvinylpyrrolidone; alginate such as alginic acid or a salt of alginic acid such as sodium alginate; a clay such as Veegum ^® HV (magnesium aluminum silicate); a gum such as agar, guar, locust bean, Karaya, pectin, or tragacanth;

sodium starch glycolate; bentonite; a natural sponge; a surfactant; a resin such as a cation- exchange resin; citrus pulp; sodium lauryl sulfate; sodium lauryl sulfate in combination starch; and the like.

[00394] In some embodiments, the dispersing agents suitable for the aqueous suspensions and dispersions described herein are known in the art and include, for example, hydrophilic polymers, electrolytes, Tween ^® 60 or 80, PEG, polyvinylpyrrolidone (PVP; commercially known as Plasdone ), and the carbohydrate-based dispersing agents such as, for example, hydroxypropylcellulose and hydroxypropyl cellulose ethers (e.g., HPC, HPC-SL, and HPC-L), hydroxypropyl methylcellulose and hydroxypropyl methylcellulose ethers (e.g. HPMC K100, HPMC K4M, HPMC K15M, and HPMC K100M), carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylmethyl-cellulose phthalate, hydroxypropylmethyl-cellulose acetate stearate, noncrystalline cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol (PVA), polyvinylpyrrolidone/vinyl acetate copolymer (Plasdone ^® , e.g., S-630), 4-(l,l,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde (also known as tyloxapol), poloxamers (e.g., Pluronics F68 ^® , F88 ^® , and F108 ^® , which are block copolymers of ethylene oxide and propylene oxide); and poloxamines (e.g., Tetronic 908 ^® , also known as Poloxamine 908 ^® , which is a

tetrafunctional block copolymer derived from sequential addition of propylene oxide and ethylene oxide to ethylenediamine (BASF Corporation, Parsippany, N.J.)). In other embodiments, the dispersing agent is selected from a group not comprising one of the following agents: hydrophilic polymers; electrolytes; Tween ^® 60 or 80; PEG;

polyvinylpyrrolidone (PVP); hydroxypropylcellulose and hydroxypropyl cellulose ethers (e.g., HPC, HPC-SL, and HPC-L); hydroxypropyl methylcellulose and hydroxypropyl methylcellulose ethers (e.g. HPMC K100, HPMC K4M, HPMC K15M, HPMC K100M, and Pharmacoat ^® USP 2910 (Shin-Etsu)); carboxymethylcellulose sodium; methylcellulose;

hydroxyethylcellulose; hydroxypropylmethyl-cellulose phthalate; hydroxypropylmethyl- cellulose acetate stearate; non-crystalline cellulose; magnesium aluminum silicate;

triethanolamine; polyvinyl alcohol (PVA); 4-(l, l,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide and formaldehyde; poloxamers (e.g., Pluronics F68 ^® , F88 ^® , and F108 ^® , which are block copolymers of ethylene oxide and propylene oxide); or poloxamines (e.g., Tetronic 908 ^® , also known as Poloxamine 908 ^® ).

[00395] Wetting agents suitable for the aqueous suspensions and dispersions described herein are known in the art and include, but are not limited to, cetyl alcohol, glycerol monostearate, poly oxy ethylene sorbitan fatty acid esters (e.g., the commercially available Tweens ^® such as e.g., Tween 20 ^® and Tween 80 ^® (ICI Specialty Chemicals)), and

polyethylene glycols (e.g., Carbowaxs 3350 ^® and 1450 ^® , and Carbopol 934 ^® (Union

Carbide)), oleic acid, glyceryl monostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monolaurate, sodium oleate, sodium lauryl sulfate, sodium docusate, triacetin, vitamin E TPGS, sodium taurocholate, simethicone, phosphotidylcholine and the like. [00396] Suitable preservatives for the aqueous suspensions or dispersions described herein include, for example, potassium sorbate, parabens (e.g., methylparaben and

propylparaben), benzoic acid and its salts, other esters of parahydroxybenzoic acid such as butylparaben, alcohols such as ethyl alcohol or benzyl alcohol, phenolic compounds such as phenol, or quaternary compounds such as benzalkonium chloride. Preservatives, as used herein, are incorporated into the dosage form at a concentration sufficient to inhibit microbial growth.

[00397] Suitable viscosity enhancing agents for the aqueous suspensions or dispersions described herein include, but are not limited to, methyl cellulose, xanthan gum,

carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, Plasdon ^® S-630, carbomer, polyvinyl alcohol, alginates, acacia, chitosans and combinations thereof. The concentration of the viscosity enhancing agent will depend upon the agent selected and the viscosity desired.

[00398] Examples of sweetening agents suitable for the aqueous suspensions or dispersions described herein include, for example, acacia syrup, acesulfame K, alitame, anise, apple, aspartame, banana, Bavarian cream, berry, black currant, butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream, cotton candy, cocoa, cola, cool cherry, cool citrus, cyclamate, cylamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger, glycyrrhetinate, glycyrrhiza (licorice) syrup, grape, grapefruit, honey, isomalt, lemon, lime, lemon cream,

monoammonium glyrrhizinate (MagnaSweet ^® ), maltol, mannitol, maple, marshmallow, menthol, mint cream, mixed berry, neohesperidine DC, neotame, orange, pear, peach, peppermint, peppermint cream, Prosweet ^® Powder, raspberry, root beer, rum, saccharin, safrole, sorbitol, spearmint, spearmint cream, strawberry, strawberry cream, stevia, sucralose, sucrose, sodium saccharin, saccharin, aspartame, acesulfame potassium, mannitol, talin, sucralose, sorbitol, swiss cream, tagatose, tangerine, thaumatin, tutti fruitti, vanilla, walnut, watermelon, wild cherry, wintergreen, xylitol, or any combination of these flavoring ingredients, e.g., anise-menthol, cherry-anise, cinnamon-orange, cherry-cinnamon, chocolate- mint, honey-lemon, lemon-lime, lemon-mint, menthol-eucalyptus, orange-cream, vanilla- mint, and mixtures thereof. In one embodiment, the aqueous liquid dispersion can comprise a sweetening agent or flavoring agent in a concentration ranging from about 0.001% to about 1.0% the volume of the aqueous dispersion. In another embodiment, the aqueous liquid dispersion can comprise a sweetening agent or flavoring agent in a concentration ranging from about 0.005%) to about 0.5% the volume of the aqueous dispersion. In yet another embodiment, the aqueous liquid dispersion can comprise a sweetening agent or flavoring agent in a concentration ranging from about 0.01% to about 1.0% the volume of the aqueous dispersion.

[00399] In addition to the additives listed above, the liquid formulations can also include inert diluents commonly used in the art, such as water or other solvents, solubilizing agents, and emulsifiers. Exemplary emulsifiers are ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3- butyleneglycol, dimethylformamide, sodium lauryl sulfate, sodium doccusate, cholesterol, cholesterol esters, taurocholic acid, phosphotidylcholine, oils, such as cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil, and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, fatty acid esters of sorbitan, or mixtures of these substances, and the like.

[00400] In some embodiments, the pharmaceutical formulations described herein can be self-emulsifying drug delivery systems (SEDDS). Emulsions are dispersions of one immiscible phase in another, usually in the form of droplets. Generally, emulsions are created by vigorous mechanical dispersion. SEDDS, as opposed to emulsions or microemulsions, spontaneously form emulsions when added to an excess of water without any external mechanical dispersion or agitation. An advantage of SEDDS is that only gentle mixing is required to distribute the droplets throughout the solution. Additionally, water or the aqueous phase can be added just prior to administration, which ensures stability of an unstable or hydrophobic active ingredient. Thus, the SEDDS provides an effective delivery system for oral and parenteral delivery of hydrophobic active ingredients. In some embodiments, SEDDS provide improvements in the bioavailability of hydrophobic active ingredients. Methods of producing self-emulsifying dosage forms are known in the art and include, but are not limited to, for example, U.S. Pat. Nos. 5,858,401, 6,667,048, and 6,960,563, each of which is specifically incorporated by reference.

[00401] It is to be appreciated that there is overlap between the above-listed additives used in the aqueous dispersions or suspensions described herein, since a given additive is often classified differently by different practitioners in the field, or is commonly used for any of several different functions. Thus, the above-listed additives should be taken as merely exemplary, and not limiting, of the types of additives that can be included in formulations described herein. The amounts of such additives can be readily determined by one skilled in the art, according to the particular properties desired.

Intranasal Formulations [00402] Intranasal formulations are known in the art and are described in, for example,

U.S. Pat. Nos. 4,476, 116, 5,116,817 and 6,391,452, each of which is specifically incorporated by reference. Formulations that include ibrutinib, which are prepared according to these and other techniques well-known in the art are prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, fluorocarbons, and/or other solubilizing or dispersing agents known in the art. See, for example, Ansel, H. C. et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, Sixth Ed. (1995). Preferably these compositions and

formulations are prepared with suitable nontoxic pharmaceutically acceptable ingredients. These ingredients are known to those skilled in the preparation of nasal dosage forms and some of these can be found in Remington: The Science and Practice of Pharmacy, 21st edition, 2005, a standard reference in the field. The choice of suitable carriers is highly dependent upon the exact nature of the nasal dosage form desired, e.g., solutions, suspensions, ointments, or gels. Nasal dosage forms generally contain large amounts of water in addition to the active ingredient. In some embodiments, minor amounts of other ingredients such as pH adjusters, emulsifiers or dispersing agents, preservatives, surfactants, gelling agents, or buffering and other stabilizing and solubilizing agents are also present. The nasal dosage form should be isotonic with nasal secretions.

[00403] In some embodiments, for administration by inhalation described herein, the pharmaceutical compositions are in a form as an aerosol, a mist or a powder. Pharmaceutical compositions described herein are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In some embodiments, in the case of a pressurized aerosol, the dosage unit is determined by providing a valve to deliver a metered amount. In some embodiments, capsules and cartridges of, such as, by way of example only, gelatin for use in an inhaler or insufflator are formulated containing a powder mix of the compound described herein and a suitable powder base such as lactose or starch.

Buccal Formulations

[00404] In some embodiments, buccal formulations are administered using a variety of formulations known in the art. For example, such formulations include, but are not limited to, U.S. Pat. Nos. 4,229,447, 4,596,795, 4,755,386, and 5,739, 136, each of which is specifically incorporated by reference. In addition, the buccal dosage forms described herein can further include a bioerodible (hydrolysable) polymeric carrier that also serves to adhere the dosage form to the buccal mucosa. The buccal dosage form is fabricated so as to erode gradually over a predetermined time period, wherein the delivery is provided essentially throughout. Buccal drug delivery, as will be appreciated by those skilled in the art, avoids the

disadvantages encountered with oral drug administration, e.g., slow absorption, degradation of the active agent by fluids present in the gastrointestinal tract and/or first-pass inactivation in the liver. With regard to the bioerodible (hydrolysable) polymeric carrier, it will be appreciated that virtually any such carrier can be used, so long as the desired drug release profile is not compromised, and the carrier is compatible with ibrutinib, and any other components that are present in the buccal dosage unit. Generally, the polymeric carrier comprises hydrophilic (water-soluble and water-swellable) polymers that adhere to the wet surface of the buccal mucosa. Examples of polymeric carriers useful herein include acrylic acid polymers and co, e.g., those known as "carbomers" (Carbopol ^® , which can be obtained from B.F. Goodrich, is one such polymer). In some embodiments, other components are also incorporated into the buccal dosage forms described herein include, but are not limited to, disintegrants, diluents, binders, lubricants, flavoring, colorants, preservatives, and the like. In some embodiments, for buccal or sublingual administration, the compositions are in the form of tablets, lozenges, or gels formulated in a conventional manner.

Transdermal Formulations

[00405] In some embodiments, transdermal formulations described herein are administered using a variety of devices which have been described in the art. For example, such devices include, but are not limited to, U.S. Pat. Nos. 3,598, 122, 3,598, 123, 3,710,795, 3,731,683, 3,742,951, 3,814,097, 3,921,636, 3,972,995, 3,993,072, 3,993,073, 3,996,934, 4,031,894, 4,060,084, 4,069,307, 4,077,407, 4,201,211, 4,230,105, 4,292,299, 4,292,303, 5,336,168, 5,665,378, 5,837,280, 5,869,090, 6,923,983, 6,929,801 and 6,946,144, each of which is specifically incorporated by reference in its entirety.

[00406] In some embodiments, the transdermal dosage forms described herein incorporate certain pharmaceutically acceptable excipients which are conventional in the art. In some embodiments, the transdermal formulations described herein include at least three components: (1) a formulation of a compound of ibrutinib; (2) a penetration enhancer; and (3) an aqueous adjuvant. In addition, transdermal formulations can include additional

components such as, but not limited to, gelling agents, creams and ointment bases, and the like. In some embodiments, the transdermal formulation can further include a woven or non- woven backing material to enhance absorption and prevent the removal of the transdermal formulation from the skin. In other embodiments, the transdermal formulations described herein can maintain a saturated or supersaturated state to promote diffusion into the skin. [00407] In some embodiments, formulations suitable for transdermal administration of compounds described herein employ transdermal delivery devices and transdermal delivery patches and can be lipophilic emulsions or buffered, aqueous solutions, dissolved and/or dispersed in a polymer or an adhesive. In some embodiments, such patches are constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents. Still further, transdermal delivery of the compounds described herein can be accomplished by means of iontophoretic patches and the like. Additionally, transdermal patches can provide controlled delivery of ibrutinib. The rate of absorption can be slowed by using rate-controlling membranes or by trapping the compound within a polymer matrix or gel. Conversely, absorption enhancers can be used to increase absorption. An absorption enhancer or carrier can include absorbable pharmaceutically acceptable solvents to assist passage through the skin. For example, transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.

Injectable Formulations

[00408] In some embodiments, formulations include a combination of a Btk inhibitor

(e.g. ibrutinib) and an immunomodulating agent, suitable for intramuscular, subcutaneous, or intravenous injection include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles including water, ethanol, polyols (propyleneglycol, polyethylene-glycol, glycerol, cremophor and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. In some embodiments, formulations suitable for subcutaneous injection also contain additives such as preserving, wetting, emulsifying, and dispensing agents. Prevention of the growth of microorganisms can be ensured by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, and the like. In some embodiments, it is also desirable to include isotonic agents, such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, such as aluminum monostearate and gelatin. [00409] In some embodiments, for intravenous injections, compounds described herein are formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art. In some embodiments, for other parenteral injections, appropriate formulations include aqueous or nonaqueous solutions, preferably with physiologically compatible buffers or excipients. Such excipients are generally known in the art.

[00410] In some embodiments, parenteral injections involve bolus injection or continuous infusion. In some embodiments, formulations for injection are presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. In some embodiments, the pharmaceutical composition described herein is in a form suitable for parenteral injection as a sterile suspensions, solutions or emulsions in oily or aqueous vehicles, and contains formulatory agents such as suspending, stabilizing and/or dispersing agents. Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, in some embodiments, suspensions of the active compounds are prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. In some embodiments, aqueous injection suspensions contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, in some embodiments, the suspension also contains suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Alternatively, in some embodiments, the active ingredient is in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

Other Formulations

[00411] In certain embodiments, delivery systems for pharmaceutical compounds are employed, such as, for example, liposomes and emulsions. In certain embodiments, compositions provided herein can also include an mucoadhesive polymer, selected from among, for example, carboxymethylcellulose, carbomer (acrylic acid polymer),

poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylic acid/butyl acrylate copolymer, sodium alginate and dextran.

[00412] In some embodiments, the compounds described herein are administered topically and can be formulated into a variety of topically administrable compositions, such as solutions, suspensions, lotions, gels, pastes, medicated sticks, balms, creams or ointments. Such pharmaceutical compounds can contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.

[00413] In some embodiments, the compounds described herein are formulated in rectal compositions such as enemas, rectal gels, rectal foams, rectal aerosols, suppositories, jelly suppositories, or retention enemas, containing conventional suppository bases such as cocoa butter or other glycerides, as well as synthetic polymers such as polyvinylpyrrolidone, PEG, and the like. In suppository forms of the compositions, a low-melting wax such as, but not limited to, a mixture of fatty acid glycerides, optionally in combination with cocoa butter is first melted.

Dosing and Treatment Regimens

[00414] In some embodiments, the amount of a TEC inhibitor that is administered in combination with an immunomodulating agent is from 10 mg/day up to, and including, 1000 mg/day. In some embodiments, the TEC inhibitor is a Btk inhibitor or an Itk inhibitor. In some embodiments, the TEC inhibitor is a Btk inhibitor.

[00415] In some embodiments, the amount of the Btk inhibitor that is administered in combination with an immunomodulating agent is from 10 mg/day up to, and including, 1000 mg/day. In some embodiments, the amount of the Btk inhibitor that is administered is from about 40 mg/day to 70 mg/day. In some embodiments, the amount of the Btk inhibitor that is administered per day is about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, or about 140 mg. In some embodiments, the Btk inhibitor is ibrutinib.

[00416] In some embodiments, the amount of ibrutinib that is administered in combination with an immunomodulating agent is from 10 mg/day up to, and including, 1000 mg/day. In some embodiments, the amount of ibrutinib that is administered is from about 40 mg/day to 70 mg/day. In some embodiments, the amount of ibrutinib that is administered per day is about 10 mg, about 11 mg, about 12 mg, about 13 mg, about 14 mg, about 15 mg, about 16 mg, about 17 mg, about 18 mg, about 19 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, or about 140 mg. In some embodiments, the amount of ibrutinib that is administered is about 40 mg/day. In some embodiments, the amount of ibrutinib that is administered is about 50 mg/day. In some embodiments, the amount of ibrutinib that is administered is about 60 mg/day. In some embodiments, the amount of ibrutinib that is administered is about 70 mg/day.

[00417] In some embodiments, the AUCo-24 of ibrutinib co-administered with an immunomodulating agent is between about 50 and about 10000 ng/mL. In some

embodiments, the Cmax of ibrutinib co-administered with an immunomodulating agent is between about 5 ng/mL and about 1000 ng/mL.

[00418] In some embodiments, the amount of an immunomodulating agent described herein that is administered in combination with a TEC inhibitor (e.g. Btk inhibitor such as ibrutinib, Itk inhibitor) is from 0.001 mg/kg up to and including 500 mg/kg. In some embodiments, the amount of an immunomodulating agent that is administered is from about 0.01 mg/kg to about 100 mg/kg. In some embodiments, the amount of an immunomodulating agent that is administered is about 0.05 mg/kg, about 0.06 mg/kg, about 0.07 mg/kg, about 0.08 mg/kg, about 0.09 mg/kg, about 0.1 mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1 mg/kg, about 1.5 mg/kg, about 2 mg/kg, about 2.5 mg/kg, about 3 mg/kg, about 3.5 mg/kg, about 4 mg/kg, about 4.5 mg/kg, about 5 mg/kg, about 5.5 mg/kg, about 6 mg/kg, about 6.5 mg/kg, about 7 mg/kg, about 7.5 mg/kg, about 8 mg/kg, about 8.5 mg/kg, about 9 mg/kg, about 9.5 mg/kg, about 10 mg/kg, about 11 mg/kg, about 12 mg/kg, about 13 mg/kg, about 14 mg/kg, about 15 mg/kg, about 16 mg/kg, about 17 mg/kg, about 18 mg/kg, about 19 mg/kg, about 20 mg/kg, about 21 mg/kg, about 22 mg/kg, about 23 mg/kg, about 24 mg/kg, about 25 mg/kg, about 26 mg/kg, about 27 mg/kg, about 28 mg/kg, about 29 mg/kg, about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50 mg/kg, about 55 mg/kg, about 60 mg/kg, about 65 mg/kg, about 70 mg/kg, about 75 mg/kg, about 80 mg/kg, about 85 mg/kg, about 90 mg/kg, or about 95 mg/kg.

[00419] In some embodiments, the TEC inhibitor (e.g. Btk inhibitor, Itk inhibitor) is administered once per month, twice per month, three times per month, every other week, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, every other day, daily, twice a day, three times a day or more frequent, continuously over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more. In some

embodiments, the TEC inhibitor is a Btk inhibitor. In some embodiments, the Tec inhibitor is administered once per day for at least 7 days. In some embodiments, the Tec inhibitor is administered once per day for at least 10 days, at least 14 days, at least 21 days, at least 28 days, at least 30 days, at least 35 days, at least 42 days, at least 49 days, at least 56 days, at least 60 days, at least 70 days, or at least 90 days.

[00420] In some embodiments, the Btk inhibitor is administered once per month, twice per month, three times per month, every other week, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, every other day, daily, twice a day, three times a day or more frequent, continuously over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more. In some embodiments, the Btk inhibitor is administered once per day for at least 7 days. In some embodiments, the Btk inhibitor is administered once per day for at least 10 days, at least 14 days, at least 21 days, at least 28 days, at least 30 days, at least 35 days, at least 42 days, at least 49 days, at least 56 days, at least 60 days, at least 70 days, or at least 90 days. In some embodiments, the Btk inhibitor is ibrutinib.

[00421] In some embodiments, ibrutinib is administered once per month, twice per month, three times per month, every other week, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, every other day, daily, twice a day, three times a day or more frequent, continuously over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more. In some embodiments, the ibrutinib is administered once per day for at least 7 days. In some embodiments, the ibrutinib is administered once per day for at least 10 days, at least 14 days, at least 21 days, at least 28 days, at least 30 days, at least 35 days, at least 42 days, at least 49 days, at least 56 days, at least 60 days, at least 70 days, or at least 90 days. [00422] In some embodiments, ibrutinib is administered once per day, twice per day, or three times per day. In some embodiments, ibrutinib is administered once per day.

[00423] In some embodiments, an immunomodulating agent is administered once per month, twice per month, three times per month, every other week, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, every other day, daily, twice a day, three times a day or more frequent, continuously over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more. In some embodiments, the immunomodulating agent is administered once per day for at least 7 days. In some embodiments, the

immunomodulating agent is administered once per day for at least 10 days, at least 14 days, at least 21 days, at least 28 days, at least 30 days, at least 35 days, at least 42 days, at least 49 days, at least 56 days, at least 60 days, at least 70 days, or at least 90 days. In some embodiments, the immunomodulating agent is administered once every two days for at least 5 days, at least 7 days, at least 10 days, at least 14 days, at least 21 days, at least 28 days, at least 30 days, at least 35 days, at least 42 days, at least 49 days, at least 56 days, at least 60 days, at least 70 days, or at least 90 days.

[00424] In some embodiments, the immunomodulating agent is administered once per day, twice per day, or three times per day. In some embodiments, the immunomodulating agent is administered once per day. In some embodiments, the immunomodulating agent is administered once every two days.

[00425] In some embodiments, a TEC inhibitor (e.g. Btk inhibitor, Itk inhibitor) and an immunomodulating agent are administered sequentially or simultaneously once per month, twice per month, three times per month, every other week, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, every other day, daily, twice a day, three times a day or more frequent, continuously over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more. In some embodiments, the immunomodulating agent and the Tec inhibitor are administered sequentially or simultaneously once per day for at least 7 days. In some embodiments, the administering comprises daily dosing of the

immunomodulating agent and the Btk inhibitor for at least 10 days, at least 14 days, at least 21 days, at least 28 days, at least 30 days, at least 35 days, at least 42 days, at least 49 days, at least 56 days, at least 60 days, at least 70 days, or at least 90 days. In some embodiments, the TEC inhibitor is a Btk inhibitor.

[00426] In some embodiments, the Btk inhibitor and an immunomodulating agent are administered sequentially or simultaneously once per month, twice per month, three times per month, every other week, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, every other day, daily, twice a day, three times a day or more frequent, continuously over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more. In some embodiments, the immunomodulating agent and the Btk inhibitor are administered sequentially or simultaneously once per day for at least 7 days. In some embodiments, the administering comprises daily dosing of the immunomodulating agent and the Btk inhibitor for at least 10 days, at least 14 days, at least 21 days, at least 28 days, at least 30 days, at least 35 days, at least 42 days, at least 49 days, at least 56 days, at least 60 days, at least 70 days, or at least 90 days. In some embodiments, the Btk inhibitor is ibrutinib.

[00427] In some embodiments, ibrutinib and an immunomodulating agent are administered sequentially or simultaneously once per month, twice per month, three times per month, every other week, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, every other day, daily, twice a day, three times a day or more frequent, continuously over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more. In some embodiments, the administering comprises daily dosing of the

immunomodulating agent and ibrutinib for at least 7 days. In some embodiments, the administering comprises daily dosing of the immunomodulating agent and the Btk inhibitor for at least 10 days, at least 14 days, at least 21 days, at least 28 days, at least 30 days, at least 35 days, at least 42 days, at least 49 days, at least 56 days, at least 60 days, at least 70 days, or at least 90 days.

[00428] In some instances, a TEC inhibitor (e.g. Btk inhibitor such as ibrutinib, Itk inhibitor) is administered following a scheduled regimen while an immunomodulating agent is administered intermittently. In other instances, a TEC inhibitor (e.g. Btk inhibitor such as ibrutinib, Itk inhibitor) is administered intermittently while an immunomodulating agent is administered following a scheduled regimen.

[00429] In some instances, both a TEC inhibitor and an immunomodulating agent are administered intermittently. In some instances, a TEC inhibitor and an immunomodulating agent are administered intermittently with an additional anticancer agent. In some instances, the TEC inhibitor is a Btk inhibitor or an Itk inhibitor. In some instances, both a Btk inhibitor and an immunomodulating agent are administered intermittently. In some instances, a Btk inhibitor and an immunomodulating agent are administered intermittently with an additional anticancer agent. In some cases, the Btk inhibitor is ibrutinib. In some instances, both ibrutinib and an immunomodulating agent are administered intermittently. In some instances, ibrutinib and an immunomodulating agent are administered intermittently with an additional anticancer agent.

[00430] In some embodiments, a TEC inhibitor (e.g. Btk inhibitor, Itk inhibitor) and the immunomodulating agent are co-administered (e.g., in a single dosage form) with an additional anticancer agent, once per month, twice per month, three times per month, every other week, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, every other day, daily, twice a day, three times a day or more frequent, continuously over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more. In some embodiments, the administering comprises daily dosing of the immunomodulating agent and the Tec inhibitor are co-administered with an additional anticancer agent for at least 7 days. In some embodiments, the administering comprises daily dosing of the immunomodulating agent, the Tec inhibitor, and the additional anticancer agent for at least 10 days, at least 14 days, at least 21 days, at least 28 days, at least 30 days, at least 35 days, at least 42 days, at least 49 days, at least 56 days, at least 60 days, at least 70 days, or at least 90 days. In some embodiments, the TEC inhibitor is a Btk inhibitor. [00431] In some embodiments, a Btk inhibitor (e.g. ibrutinib) and the immunomodulating agent are co-administered (e.g., in a single dosage form) with an additional anticancer agent, once per month, twice per month, three times per month, every other week, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, every other day, daily, twice a day, three times a day or more frequent, continuously over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more. In some embodiments, the administering comprises daily dosing of the immunomodulating agent, the Btk inhibitor, and the additional anticancer agent for at least 7 days. In some embodiments, the administering comprises daily dosing of the immunomodulating agent, the Btk inhibitor, and the additional anticancer agent for at least 10 days, at least 14 days, at least 21 days, at least 28 days, at least 30 days, at least 35 days, at least 42 days, at least 49 days, at least 56 days, at least 60 days, at least 70 days, or at least 90 days.

[00432] In some embodiments, the pharmaceutical combination and/or compositions described herein are administered to treatment-naive cancer patients. In some embodiments, a treatment-naive cancer patient is a patient who has not received a treatment related to a cancer, a patient who has not received a TEC inhibitor (e.g. Btk inhibitor such as ibrutinib, Itk inhibitor) treatment, a patient who has not received an immunomodulating agent, or a patient who has not received any combinations of a TEC inhibitor, immunomodulating agent, and/or an additional anticancer agent described elsewhere herein.

[00433] In some embodiments, the pharmaceutical combination and/or compositions described herein are administered to cancer patients who have already received one or more prior treatments. In some embodiments, the one or more prior treatments include treatments such as surgery, chemotherapy, radiation therapy, and include treatments with one or more of the anticancer agents described elsewhere herein.

[00434] In some embodiments, the pharmaceutical combination and/or compositions disclosed herein are administered to patients for prophylactic, therapeutic, or maintenance treatment. In some embodiments, the compositions disclosed herein are administered for therapeutic applications. In some embodiments, the compositions disclosed herein are administered for therapeutic applications. In some embodiments, the compositions disclosed herein are administered as a maintenance therapy, for example for a patient in remission. [00435] In some embodiments, a TEC inhibitor (e.g. Btk inhibitor, Itk inhibitor) and the immunomodulating agent are administered as a maintenance therapy. In some instances, the TEC inhibitor is a Btk inhibitor. In some embodiments, the Btk inhibitor and the immunomodulating agent are administered as a maintenance therapy. In some instances, the Btk inhibitor is ibrutinib. In some embodiments, ibrutinib and the immunomodulating agent are administered as a maintenance therapy.

[00436] In the case wherein the patient's status does improve, upon the doctor's discretion the administration of the compounds may be given continuously; alternatively, the dose of drug being administered may be temporarily reduced or temporarily suspended for a certain length of time (i.e., a "drug holiday"). The length of the drug holiday can vary between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. The dose reduction during a drug holiday may be from 10%- 100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

[00437] Once improvement of the patient's conditions has occurred, a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of

administration, or both, can be reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. Patients can, however, require

intermittent treatment on a long-term basis upon any recurrence of symptoms.

[00438] The amount of a given agent that will correspond to such an amount will vary depending upon factors such as the particular compound, the severity of the disease, a biomarker profile (e.g. Thl :Th2 ratio, or any of the biomarkers described herein), the identity (e.g., weight) of the subject or host in need of treatment, but can nevertheless be routinely determined in a manner known in the art according to the particular circumstances

surrounding the case, including, e.g., the specific agent being administered, the route of administration, and the subject or host being treated. In general, however, doses employed for adult human treatment will typically be in the range of 0.02-5000 mg per day, or from about 1-1500 mg per day. The desired dose may conveniently be presented in a single dose or as divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, for example as two, three, four or more sub-doses per day.

[00439] The pharmaceutical combination and/or composition described herein may be in unit dosage forms suitable for single administration of precise dosages. In unit dosage form, the formulation is divided into unit doses containing appropriate quantities of one or more compound. The unit dosage may be in the form of a package containing discrete quantities of the formulation. Non-limiting examples are packaged tablets or capsules, and powders in vials or ampoules. Aqueous suspension compositions can be packaged in single-dose non- reclosable containers. Alternatively, multiple-dose reclosable containers can be used, in which case it is typical to include a preservative in the composition. By way of example only, formulations for parenteral injection may be presented in unit dosage form, which include, but are not limited to ampoules, or in multi-dose containers, with an added preservative.

[00440] The foregoing ranges are merely suggestive, as the number of variables in regard to an individual treatment regime is large, and considerable excursions from these recommended values are not uncommon. Such dosages may be altered depending on a number of variables, not limited to the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.

[00441] Toxicity and therapeutic efficacy of such therapeutic regimens can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between the toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD50 and ED50. Compounds exhibiting high therapeutic indices are preferred. The data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in human. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with minimal toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.

Kits/Articles of Manufacture

[00442] For use in the therapeutic methods of use described herein, kits and articles of manufacture are also described herein. Such kits include a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) comprising one of the separate elements to be used in a method described herein. Suitable containers include, for example, bottles, vials, syringes, and test tubes. In one embodiment, the containers are formed from a variety of materials such as glass or plastic.

[00443] The articles of manufacture provided herein contain packaging materials.

Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, bags, containers, bottles, and any packaging material suitable for a selected formulation and intended mode of administration and treatment.

[00444] For example, the container(s) include ibrutinib, optionally in a composition or in combination with an immunomodulating agent as disclosed herein. Such kits optionally include an identifying description or label or instructions relating to its use in the methods described herein.

[00445] A kit typically includes labels listing contents and/or instructions for use, and package inserts with instructions for use. A set of instructions will also typically be included.

[00446] In one embodiment, a label is on or associated with the container. In one embodiment, a label is on a container when letters, numbers or other characters forming the label are attached, molded or etched into the container itself; a label is associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert. In one embodiment, a label is used to indicate that the contents are to be used for a specific therapeutic application. The label also indicates directions for use of the contents, such as in the methods described herein.

[00447] In certain embodiments, the pharmaceutical combinations and/or compositions are presented in a pack or dispenser device which contains one or more unit dosage forms containing a compound provided herein. The pack, for example, contains metal or plastic foil, such as a blister pack. In one embodiment, the pack or dispenser device is accompanied by instructions for administration. In one embodiment, the pack or dispenser is also

accompanied with a notice associated with the container in form prescribed by a

governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, is the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. In one embodiment, compositions containing a compound provided herein formulated in a compatible

pharmaceutical carrier are also prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

EXAMPLES

[00448] The following ingredients, formulations, processes and procedures for practicing the methods disclosed herein correspond to that described above.

Example 1: Ibrutinib Enhances the Anti-tumor Efficacy of CTLA-4 Blockade in

Lymphoma and Colon Cancer Models [00449] In the present study, it was investigated whether ibrutinib could enhance the anti-tumor effect of an anti-mouse CTLA-4 antibody (aCTLA-4 or ipilimumab) in the A20 B-cell lymphoma and the CT26 colon cancer models.

Methods

Cell lines and animal studies

[00450] A20 B-cell lymphoma and the CT26 colon carcinoma are tumor cell lines syngeneic to the BALB/c mice. Cells were cultured in complete media (RPMI media supplemented with 10% fetal bovine serum, antibiotics and 55 μΜ 2-mercaptoethanol). A20 cells express Btk but are insensitive to ibrutinib in vitro (IC ₅₀ >10 mM). Mice were implanted subcutaneously on the back with 5 x 10 ⁶ A20 cells or on the flank with 5 x 10 ⁵ CT26 cells on day 0. Treatment began when the average tumor volume reached 80-85 mm (D x d ² x 0.4). Mice were dosed daily with oral ibrutinib (24 mg/kg) or vehicle and the anti-mouse CTLA-4 antibody 9D9 (Bio X Cell), or an IgG isotype control (100 μg/mouse) given every 2 days by intraperitoneal injections. Tumor volume was measured and survival recorded for up to 2 months after tumor inoculation. Animals were euthanized when tumors reached 2000 mm ³ per IACUC protocol.

IFN-γ ELISA

[00451] Single-cell suspensions of spleens were treated with ACK lysis buffer to remove red blood cells. Tumor cells were incubated at 37°C for 20 min in complete media containing 50 μg/mL mitomycin C followed by washing. Each well of a 96-well round bottom plate was seeded with 5 x 10 ⁵ splenocytes with or without 5 X 10 ⁵ mitomycin C- treated tumor cells in complete media containing 5% serum and 0.5 μg/mL anti-mouse CD28 antibody. After 48 h of culture, the concentration of IFN-γ in the supernatant was determined using the Mouse IFN-gamma Quantikine ELISA Kit (R&D Systems).

Flow cytometry analysis of TILs

[00452] CT26 tumors were harvested on the 6 ^th day of treatment, weighed, minced, and reduced to single-cell suspensions on 70 mm strainers. A majority of the tumor cells, red blood cells, and debris were removed by density gradient centrifugation using Lympholyte®- M (Cedarlane Labs). The partially purified tumor-infiltrating leukocytes were incubated for 3 h with complete media containing GolgiStop™ (BD Biosciences). Cells were then Fc- blocked, incubated with fixable aqua dead cell stain (Life Technologies), stained with fluorochrome-labeled antibodies for surface and intracellular markers, and fixed with 1% paraformaldehyde. Cells samples with CountBright™ Counting Beads (Life Technologies) were acquired on a FACSCanto™ II cytometer (BD Biosciences). Data were analyzed using the FlowJo VI 0 software (Flow Jo, LLC)

Results

[00453] As provided herein in the B-cell lymphoma model, aCTLA-4 had single-agent activity, while aCTLA-4 + ibrutinib led to more rapid and durable responses.

[00454] Figures 1 A-1E show that ibrutinib enhanced the therapeutic efficacy of aCTLA-4 against the A20 B-cell lymphoma. Mice implanted subcutaneously with A20 cells received ibrutinib or vehicle (PO, QD x 13) and 100 mg aCTLA-4 or IgG (IP, Q2D x 6) from days 5 to 17 (arrows). The number of animals that remained tumor-free as of day 68 is indicated in the plot.

[00455] As provided herein in the colon cancer model, aCTLA-4 was not effective in controlling the disease, but aCTLA-4 + ibrutinib led to the regression of many large tumors. In addition, aCTLA-4 + ibrutinib increased tumor infiltration by CD4 ⁺ and CD8 ⁺ T cells, many are Ki-67 ⁺ and IFN-Y ⁺ . 60% of animals treated with the combination remained disease- free until the end of study, and aCTLA-4 + ibrutinib generated a robust, tumor-specific immunologic memory.

[00456] Figures 2A-2G show that ibrutinib enhanced the therapeutic efficacy of aCTLA-4 against the CT26 colon carcinoma. Mice implanted sc with CT26 cells received ibrutinib or vehicle (PO, QD x 27) and 100 mg aCTLA-4 or IgG (IP, Q2D x 17) from day 7- 42 (arrows, schedule 1 (S I)). S2 regimen was identical to S I except that ibrutinib treatment began on day 1 1. The number of animals that remained tumor-free on day 73 are indicated (* O.003).

[00457] Figure 3 shows that aCTLA-4 + ibrutinib generated a robust, tumor-specific immunologic memory. Spleens were harvested on day 73 from naive animals or from tumor- free animals on the study described in Fig. 2. Splenocytes were co-cultured with CT26 cells, irrelevant 4T1 cells, or with media alone for 48 h. The concentration of IFN-γ secreted into the culture media was measured by ELISA.

[00458] Figures 4A-4R show that aCTLA-4 + ibrutinib increased tumor infiltration by

Ki-67 ⁺ /IFN-y ⁺ CD4 ⁺ and CD8 ⁺ T cells. Mice (6/group) implanted subcutaneously with CT26 cells received ibrutinib or vehicle (PO, QD x 5) and 100 μg aCTLA-4 or IgG (IP, Q2D x 3) from days 7-12 (arrows, S I). S2 regimen was identical to S I except that ibrutinib treatment began on day 1 1. Animals were sacrificed on day 13 (dotted lines) (Fig. 4A). Tumors were harvested for flow cytometry analysis of tumor-infiltrating T cells. On the scattered dot plots, the dots that correspond to the top 3 responders of each group are circled and labeled with rankings. Response to a treatment was judged primarily by the final size of the tumor, and secondarily by the growth rate of the tumor between the last 2 measurements (Figs. 4A-4Q). Spleens were harvested from 3 naive animals or from treated animals (6/group) on day 13. Splenocytes were co-cultured with CT26 cells, irrelevant 4T1 cells, or with media alone for 48 h. The concentration of IFN-γ secreted into the culture media was measured by ELISA. The dots that correspond to the top 3 responders of each group are circled and labeled with rankings. Response to a treatment is judged primarily by the final size of the tumor, and secondarily by the growth rate of the tumor between the last 2 measurements (Fig. 4R).

[00459] As provided herein, ibrutinib enhanced the therapeutic efficacy of aCTLA-4 in models of B-cell lymphoma and colon carcinoma. Combination therapy increased tumor infiltration by both helper and cytotoxic T cells. Combination therapy also generated a robust, tumor-specific immunologic memory. These data suggested that ibrutinib synergizes with immunomodulating agents/therapies (i.e., T-cell modulating therapies) to treat hematologic and solid tumors.

Example 2: The combination of ibrutinib and CTLA-4, PD-1, and PD-Ll inhibitors on responses in syngeneic murine solid tumor models

[00460] In this example, reference is made to Figures 6A-10E. Immunocompetent mice with matched genetic backgrounds were subcutaneously inoculated in the right flank with syngenic tumor cells from the following murine solid tumor models: Pan02 (pancreatic cancer); Renca (renal cell carcinoma); MBT-2 (bladder cancer); and MC38 (colon cancer). Treatment began when mean tumor size reached approximately 70-100 mm ³ .

[00461] Tumor and blood samples were collected at the tumor site or in peripheral compartments for tumor measurement by caliper and cytokine analysis by a Meso Scale Discovery (MSD) assay or a Luminex® Multiplex assay.

[00462] The effect of treatment on mouse tumor volume was measured in two dimensions using calipers and calculated with the following formula: tumor volume (mm ³ ) = ½ (tumor width[mm] ² x length [mm]).

[00463] Tumors were measured twice per week until study termination on day 60.

Mice were individually monitored and euthanized when tumor volume reached the endpoint of 2000 mm ³ , or on the final day (day 60), whichever came first. The amount of time to reach the endpoint (tumor volume of 2000 mm ³ ) was measured for each mouse. Statistical analysis of sample t-tests and 1-way ANOVA (one-way analysis of variance) were used to make comparisons amongst groups. Ibrutinib and immunomodulating agent (anti-PD-1; anti-PD-Ll, or anti-CTLA-4) in mouse MBT-2 bladder cancer model

[00464] Ibrutinib was administered alone (orally, 48 mg/kg, once daily for 21 days); or in combination with one of the following immunomodulating agents: (1) anti-PD-1

(intrapentoneally, 100 μg/mouse, twice weekly for 3 weeks); (2) anti-PD-Ll

(intrapentoneally, 100 μg/mouse; twice weekly for 3 weeks); or (3) anti-CTLA-4

(intrapentoneally, 100 μg/mouse [day 1], 50 μg/mouse [days 4, 7, 10, and 13]).

[00465] As shown in Figures 6a and 6c, the administration of ibrutinib, either alone or in combination with PD-1 or CTLA-4 inhibitors, decreased tumor growth. Additionally, administration of a combination of ibrutinib and anti-PD-1 or a combination of ibrutinib and anti-CTLA-4, decreased tumor growth to a greater extent than administration of anti-PD-1 or anti-CTLA-4 alone.

[00466] As shown in Figures 6b, 6d, and 6e, administration of ibrutinib, either alone or in combination with an immunomodulating agent such as anti-CTLA-4, decreased T Fa levels.

Ibrutinib and immunomodulating agent (anti-PD-Ll) in mouse MBT-2 bladder cancer model

[00467] Ibrutinib was administered alone (orally, 48 mg/kg, once daily for 21 days), or in combination with anti-PD-Ll (intraperitoneally, 100 μg/mouse; twice weekly for 3 weeks). As shown in Figure 7, administration of ibrutinib, with PD-L1 inhibitor, improved survival, compared to administration of PD-L1 inhibitor alone.

Effect of ibrutinib with or without CTLA-4, PD-L or PD-L1 inhibitors on cytokine production and tumor growth in the mouse MC38 colorectal cancer model

[00468] Reference is made to Figures 8A-10E. Ibrutinib was administered alone

(orally at 48 mg/kg, once daily for 28 days), or in combination with one of the following immunomodulating agents: (1) anti-PD-1 (intraperitoneally, 100 μg/mouse, twice weekly for 3 weeks); (2) anti-PD-Ll (intraperitoneally, 100 μg/mouse; twice weekly for 3 weeks); or (3) anti-CTLA-4 (intraperitoneally, 100 μg/mouse, [day 1], 50 μg/mouse [days 4, 7, 10, and 13].

[00469] As shown in Figs. 8 A, 9A, and 10A, ibrutinib, with our without an

immunomodulating agent (anti-PD-1; anti-PD-Ll, or anti-CTLA-4), decreased tumor growth in the mouse MC38 colorectal model. Complete regression of established M38 tumors was observed with ibrutinib in combination with anti-CTLA-4. [00470] Figures 8D-E, 9D-E, and 10D-E show the effect of treatment on the secretion of VEGF and TNF-a in the mouse MC38 colorectal model. As shown in Figs. 10D-E, administration of the combination of ibrutinib and anti-CTLA-4 decreased the secretion of both TNF-a and VEGF, compared to the administration of anti-CTLA-4 alone. As shown in FIG. 9D, administration of the combination of ibrutinib and anti-PD-Ll decreased the secretion of both TNF-a and VEGF, compared to the administration of anti-PD-Ll alone.

[00471] As shown in Fig. IOC, administration of the combination of ibrutinib and anti-

CTLA-4 improves survival in the mouse MC38 colorectal model.

[00472] The examples and embodiments described herein are illustrative and various modifications or changes suggested to persons skilled in the art are to be included within this disclosure. As will be appreciated by those skilled in the art, the specific components listed in the above examples may be replaced with other functionally equivalent components, e.g., diluents, binders, lubricants, fillers, and the like.